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Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies

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• Review Article
• Open access
• Published: 23 August 2024

Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies

• Jifa Zhang, 
• Yinglu Zhang, 
• Jiaxing Wang, 
• Yilin Xia, 
• Jiaxian Zhang & 
• Lei Chen 

Signal Transduction and Targeted Therapy volume 9, Article number: 211 (2024) Cite this article

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Abstract

Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. In the past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available drugs primarily offer symptomatic relief and often accompanied by undesirable side effects. However, recent approvals of aducanumab (1) and lecanemab (2) by the Food and Drug Administration (FDA) present the potential in disrease-modifying effects. Nevertheless, the long-term efficacy and safety of these drugs need further validation. Consequently, the quest for safer and more effective AD drugs persists as a formidable and pressing task. This review discusses the current understanding of AD pathogenesis, advances in diagnostic biomarkers, the latest updates of clinical trials, and emerging technologies for AD drug development. We highlight recent progress in the discovery of selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, proteolysis-targeting chimeras (PROTACs), and protein-protein interaction (PPI) modulators. Our goal is to provide insights into the prospective development and clinical application of novel AD drugs.

요약

알츠하이머병(AD)은 치매의 가장 흔한 형태로, 전 세계적으로 심각하고 확대되는 문제를 야기하고 있습니다. 그 원인은 복잡하고 다양하며 노화, 유전, 환경 등 여러 요인이 복합적으로 작용하여 발생합니다.

현재 AD 병리에 대한 이해에는

콜린성, 아밀로이드, 타우 단백질, 염증, 산화 스트레스, 금속 이온,

글루타메이트 흥분 독성, 미생물-장-뇌 축, 비정상적인 자가포식 등

다양한 가설이 포함되어 있습니다.

그럼에도 불구하고 이러한 병리학적 측면 간의 상호 작용을 밝히고 알츠하이머병의 주요 발병 인자를 정확히 찾아내려면 더 많은 설명과 검증이 필요합니다. 지난 수십 년 동안 대부분의 임상 약물은 제한된 효과나 부작용으로 인해 개발이 중단되었습니다. 현재 사용 가능한 약물은 주로 증상 완화를 제공하며 종종 바람직하지 않은 부작용을 동반합니다.

그러나

최근 미국 식품의약국(FDA)에서

아두카누맙(1)과 레카네맙(2)을 승인하면서

질병을 개선할 수 있는 가능성이 제시되었습니다.

그럼에도 불구하고 이러한 약물의 장기적인 효능과 안전성에 대해서는 추가적인 검증이 필요합니다. 따라서 보다 안전하고 효과적인 AD 치료제를 찾는 일은 여전히 시급한 과제로 남아 있습니다.

이 리뷰에서는

AD 발병 기전에 대한 현재의 이해,

진단 바이오마커의 발전,

임상시험의 최신 업데이트 및 AD 약물 개발을 위한 새로운 기술에 대해 논의합니다.

선택적 억제제,

이중 표적 억제제,

알로스테릭 조절제,

공유 결합 억제제,

단백질 분해 표적 키메라(PROTAC),

단백질-단백질 상호작용(PPI) 조절제의

최근 발견에 대한 진전을 중점적으로 다룹니다.

selective inhibitors,

dual-target inhibitors,

allosteric modulators,

covalent inhibitors,

proteolysis-targeting chimeras (PROTACs), and

protein-protein interaction (PPI) modulators

우리의 목표는

새로운 AD 치료제의 잠재적 개발 및 임상 적용에 대한

인사이트를 제공하는 것입니다.

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Introduction

Dementia has emerged as a global health challenge. According to the World Health Organization’s 2022 blueprint for dementia research, an estimated 55.2 million individuals globally are affected. The preval‎ence among those over the age of 60 varies by region: with Southeast Asia reporting a preval‎ence of 2.9%, Europe at 6.5%, and other regions experiencing rates between 3.1% and 5.7%.1 The incidence of dementia is generally increasing, while some high-income countries are seeing a decline.2 By 2030, the estimated number of people living with dementia will surge to 78 million. Furthermore, the global financial burden associated with medical care, social services, and informal caregiving for those with dementia is expected to exceed US$ 2.8 trillion. This situation will have a profound impact on individuals, families, and societies.1 Alzheimer’s disease (AD), the predominant form of dementia, exhibits similar epidemiological trends and represents an urgent and escalating challenge worldwide. In the United States, approximately one in nine individuals (10.8%) age 65 and older suffer from AD, with an annual incidence of 1275 new cases per 100,000 persons.3,4 Patients with AD exhibit a substantial accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) within their brains, accompanied by a cascade of pathological processes such as neuroinflammation, synaptic dysfunction, mitochondrial and bioenergetic disturbances, as well as vascular abnormalities. Collectively these processes may ultimately lead to the death of neurons.5,6 

Clinically, the primary hallmark of AD is amnestic cognitive impairment. Initially, symptoms may manifest as depression, anxiety, social withdrawal, and altered sleep patterns. As the disease progresses, symptoms worsen, leading to severe memory loss, neuropsychiatric symptoms such as hallucinations and delusions, and intensified behavioral and emotional issues in its advanced stages. Additionally, some patients with non-amnestic cognitive impairment may experience varying levels of dysfunctions in visual-spatial, language, executive functions, behavior, or motor skills.2,7,8,9 Moreover, comorbidities linked with AD may exacerbate the health condition of patients, contributing to clinical phenotype diversity and accelerating cognitive dysfunction. Such conditions include hypercholesterolemia, hypertension, diabetes, obesity, depression, and cardiovascular diseases. Additionally, complications arising from AD progressions, like thrombosis, mobility impairments, dysphagia, malnutrition, and pneumonia (lung infections), may considerably diminish the life quality of patients and increase mortality risk.2,4,10,11,12,13,14 The connection between comorbidities and the pathological changes in AD is currently the subject of ongoing research.15,16,17 Unfortunately, there is yet no cure for AD, and patients are frequently diagnosed at a late and irreversible stage, facing an average survival period of 4–8 years.4,18,19 Nonetheless, pathological changes in the brain begin during the preclinical stage, decades before clinical symptoms. Typically, patients transit to mild cognitive impairment (MCI) around 6-10 years later, with approximately 15% progressing to AD within 2 years and one-third within 5 years.4,20,21 Therefore, it’s crucial to concentrate on the preclinical and MCI stages, where early intervention and management of modifiable risk factors could potentially lower the risk of onset or delay the progression of disease.22 Evidence suggests that about one-third of AD cases worldwide are closely linked to modifiable risk factors.23 Encouragingly, due to improvements in risk factors such as vascular health, lifestyle choices, and education levels, the incidence of AD is on a downward trend in the United States, South Korea, Europe, and certain regions of Asia.2,24 In recent years, numerous articles4,22,23,25,26,27,28 have highlighted modifiable risk factors for AD, alongside the benefits of Multidomain Alzheimer Preventive Trials. These insights underscore the efficacy of early prevention strategies for AD.

소개

치매는 전 세계적인 보건 문제로 떠오르고 있습니다. 세계보건기구의 2022년 치매 연구 청사진에 따르면, 전 세계적으로 약 5,520만 명이 치매에 걸린 것으로 추정됩니다. 60세 이상 인구의 유병률은 지역별로 차이가 있는데, 동남아시아는 2.9%, 유럽은 6.5%, 기타 지역은 3.1%에서 5.7%의 유병률을 보이고 있습니다.1 치매 발병률은 일반적으로 증가하고 있지만 일부 고소득 국가에서는 감소하고 있습니다.2 2030년에는 치매 환자 수가 7800만 명으로 급증할 것으로 예상됩니다. 또한 치매 환자를 위한 의료, 사회 서비스 및 비공식 간병과 관련된 전 세계의 재정적 부담은 2조 8,000억 달러를 넘어설 것으로 예상됩니다. 이러한 상황은 개인, 가족, 사회에 큰 영향을 미칠 것입니다.1

치매의 주요 형태인 알츠하이머병(AD)은

유사한 역학 추세를 보이며 전 세계적으로 시급하고 확대되는 과제를 나타냅니다.

미국에서는 65세 이상 인구 9명 중 1명(10.8%)이 AD를 앓고 있으며,

매년 10만 명당 1275건의 새로운 사례가 발생하고 있습니다.3,4

알츠하이머병 환자는

뇌에 아밀로이드 베타(Aβ) 플라크와 신경섬유 엉킴(NFT)이 상당히 축적되어 있으며,

신경 염증, 시냅스 기능 장애,

미토콘드리아 및 생체 에너지 장애,

혈관 이상과 같은 일련의 병리학적인 과정이 동반됩니다.

이러한 과정을 종합하면

궁극적으로 신경세포의 사멸로 이어질 수 있습니다.5,6

임상적으로 알츠하이머병의 주요 특징은 기억상실성 인지 장애입니다.

초기에는 우울증, 불안, 사회적 위축, 수면 패턴 변화 등의 증상이 나타날 수 있습니다.

질환이 진행됨에 따라 증상이 악화되어

심각한 기억 상실, 환각 및 망상과 같은 신경정신과적 증상,

행동 및 정서적 문제가 심화되는 진행 단계로 이어집니다.

또한

비기질성 인지 장애를 가진 일부 환자는

시각 공간, 언어, 실행 기능, 행동 또는 운동 능력에서

다양한 수준의 기능 장애를 경험할 수 있습니다.2,7,8,9

또한 알츠하이머병과 관련된 동반 질환은 환자의 건강 상태를 악화시켜 임상 표현형의 다양성에 기여하고 인지 기능 장애를 가속화할 수 있습니다. 이러한 질환에는 고콜레스테롤혈증, 고혈압, 당뇨병, 비만, 우울증, 심혈관 질환 등이 있습니다. 또한 혈전증, 이동성 장애, 연하 장애, 영양실조, 폐렴(폐 감염) 등 알츠하이머병 진행으로 인한 합병증은 환자의 삶의 질을 크게 저하시키고 사망 위험을 높일 수 있습니다.2,4,10,11,12,13,14 동반 질환과 알츠하이머병의 병리적 변화 사이의 연관성은 현재 계속 연구 중입니다.15,16,17 안타깝게도 아직 알츠하이머병에 대한 치료법은 없으며, 환자들은 늦고 돌이킬 수 없는 단계에서 진단되는 경우가 많아 평균 생존 기간이 4-8년에 불과합니다.4,18,19

그럼에도 불구하고 뇌의 병리적 변화는 임상 증상 수십 년 전인 전임상 단계에서 시작됩니다.

일반적으로 환자는

약 6~10년 후 경도인지장애(MCI)로 이행하며,

약 15%는 2년 이내에,

1/3은 5년 이내에 알츠하이머병으로 진행됩니다.4,20,21

따라서 수정 가능한 위험 요인에 대한 조기 개입과 관리로 발병 위험을 낮추거나 질병 진행을 지연시킬 수 있는 전임상 및 MCI 단계에 집중하는 것이 중요합니다.22 증거에 따르면 전 세계 알츠하이머병 사례의 약 1/3은 수정 가능한 위험 요인과 밀접한 관련이 있는 것으로 나타났습니다.23

고무적인 것은

혈관 건강, 생활습관, 교육 수준과 같은 위험 요인의 개선으로 인해

미국, 한국, 유럽, 아시아 일부 지역에서

알츠하이머 발병률이 감소 추세에 있다는 것입니다.2,24

최근 몇 년 동안 수많은 기사4,22,23,25,26,27,28에서 다분야 알츠하이머 예방 시험의 혜택과 함께 수정 가능한 AD의 위험 요인을 강조하고 있습니다. 이러한 인사이트는 알츠하이머 조기 예방 전략의 효능을 강조합니다.

The etiology of AD is complex and diverse, and the precise mechanisms underlying its onset are not yet completely understood. Beyond the pivotal role of Aβ and tau, a spectrum of other factors may contribute to the pathology of AD, such as acetylcholine deficiency, neuroinflammation, oxidative stress, biometal dyshomeostasis, glutamate imbalance, insulin resistance, gut microbiome abnormalities, cholesterol homeostasis disruption, mitochondrial dysfunction, and autophagy abnormalities29,30,31 (Fig. 1). Of note, these factors also form the foundation for clinical diagnosis and treatment strategies. Biomarkers can identify patients in the early stages, monitor disease progression, and eval‎uate the effectiveness of drugs.32,33,34,35 The hypotheses surrounding these pathogenic factors provide potential targets for drug development. However, the development of effective AD drugs has been fraught with challenges.

Tacrine (3)36,37,38,39,40 was withdrawn from the market primarily because of its hepatotoxicity. Medications such as donepezil (4),41,42,43 rivastigmine (5),44,45 galantamine (6),46,47,48 memantine (7),49,50 and namzaric (8)51,52 have been employed in clinical settings. While these drugs can temporarily alleviate or stabilize symptoms, they are unable to stop the long-term progression of the disease and are associated with various side effects.33,53 New drugs, including sodium oligomannate (9, GV-971),54,55,56 aducanumab (1),57,58,59 lecanemab (2),60,61,62 and donanemab (10, currently under review for market approval),63 which aim to offer disease-modifying therapies that intervene in the progression of AD. Their clinical relevance remains to be eval‎uated thoroughly. More than a century has elapsed since AD was first described in 1906,64 and significant progress has been made in understanding its pathogenesis, improving diagnosis, and enhancing treatment.65,66 Unfortunately, the current offerings fall short of meeting the need to address cognitive. Therefore, this review takes into account the AD research framework of prevention, diagnosis, and treatment, and discusses the pathogenesis, diagnostic biomarkers, clinical trials, and next-generation small molecule drugs. It also emphasizes the critical need to improve the safety and efficacy of drugs through innovative drug development techniques, such as selective inhibitors,67 dual-target inhibitors,68,69 allosteric modulators,70,71 covalent inhibitors,72 proteolysis-targeting chimeras (PROTACs)73 and protein-protein interaction (PPI) modulators,74,75 aiming for more effective clinical translation from outcomes of research.

알츠하이머병의 원인은 복잡하고 다양하며, 발병의 근본이 되는 정확한 메커니즘은 아직 완전히 밝혀지지 않았습니다.

Aβ와 타우의 중추적인 역할 외에도

아세틸콜린 결핍, 신경 염증, 산화 스트레스,

생체 항상성 이상, 글루타메이트 불균형,

인슐린 저항성, 장내 미생물 이상, 콜레스테롤 항상성 파괴,

미토콘드리아 기능 장애, 오토파지 이상 등

다양한 요인이 AD의 병리에 기여할 수 있습니다29,30,31 (그림 1).

이러한 요인들은 임상 진단 및 치료 전략의 기초를 형성하기도 합니다.

바이오마커는

초기 단계에서 환자를 식별하고

질병 진행을 모니터링하며 약물의 효과를 평가할 수 있습니다.32,33,34,35

이러한 병원성 인자를 둘러싼 가설은 약물 개발을 위한 잠재적 표적을 제공합니다. 그러나 효과적인 AD 치료제를 개발하는 데는 많은 어려움이 있습니다.

타크린(3)36,37,38,39,40은 주로 간독성 때문에 시장에서 퇴출되었습니다.

도네페질(4),41,42,43

리바스티그민(5),44,45

갈란타민(6),46,47,48

메만틴(7),49,50 및 남자릭(8)51,52 같은 약물들이

임상 환경에서 사용되었습니다.

이러한 약물은 일시적으로 증상을 완화하거나 안정시킬 수 있지만, 질병의 장기적인 진행을 막을 수 없으며 다양한 부작용과 관련이 있습니다.33,53

올리고만네이트 나트륨(9, GV-971),54,55,56 아두카누맙(1),57,58,59 레카네마브(2),60,61,62 및 도나네맙(10,

현재 시장 승인 검토 중),63 등 신약은

AD 진행에 개입하는 질병 수정 치료제를 제공하는 것을 목표로 삼고 있습니다.

이들 치료제의 임상적 관련성은 아직 철저히 평가되어야 합니다. 1906년 알츠하이머병이 처음 기술된 이후 한 세기 이상이 지났으며,64 그 동안 병인을 이해하고 진단을 개선하며 치료를 향상시키는 데 상당한 진전이 있었습니다.65,66 안타깝게도 현재 제공되는 제품들은 인지 문제를 해결하기 위한 필요성을 충족시키지 못합니다.

따라서 이 리뷰에서는 예방, 진단, 치료의 AD 연구 프레임워크를 고려하여 발병 기전, 진단 바이오마커, 임상시험 및 차세대 저분자 약물에 대해 논의합니다.

또한 선택적 억제제,67 이중 표적 억제제,68,69 알로스테릭 조절제,70,71 공유 결합 억제제,72 단백질 분해 표적 키메라(PROTAC)73 및 단백질 단백질 상호작용(PPI) 조절제,74,75 연구 결과의 보다 효과적인 임상 전환을 목표로 하는 혁신적인 신약 개발 기술을 통해 의약품의 안전성과 효능을 개선해야 한다는 점을 강조하고 있습니다.

Fig. 1

Diagram for the pathogenesis of AD, including the cholinergic hypothesis,619,620 the glutamatergic hypothesis,621 the amyloid hypothesis,622,623 the tau protein hypothesis,624,625 the inflammatory hypothesis,626,627 the microbiota-gut-brain axis hypothesis,628,629 the oxidative stress hypothesis,191 the metal ion hypothesis,630,631 and the abnormal autophagy hypothesis235

콜린성 가설,619,620 글루탐산 가설,621 아밀로이드 가설,622,623 타우 단백질 가설,624,625 염증 가설,626,627 미생물-장-뇌 축 가설,628,629 산화 스트레스 가설,191 금속 이온 가설,630,631 및 이상 자가포식 가설235을 포함한 알츠하이머 병인에 대한 도표입니다

Mechanisms of AD

Numerous hypotheses have been proposed to unravel the pathogenesis of AD, yet a unified theory remains elusive, likely due to the complex nature of AD. AD can be categorized into two main types: familial (accounting for 1-5% of AD cases) and sporadic forms (over 95% of cases).76 Familial AD (FAD) is predominantly characterized by autosomal dominant genetic mutations in amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes, typically manifesting between 30-65 years and progressing rapidly. In contrast, sporadic AD (SAD), also known as late-onset AD, usually manifests after the age of 65 and is influenced by a combination of genetic risks, environmental factors, and various comorbidities.77,78,79 Genome-wide association studies (GWAS) and genome-wide meta-analyses have identified numerous genetic risk loci associated with SAD, implicating pathways in immune response, lipid metabolism, Aβ plaque, NFTs, and endocytosis, yet many loci remain undiscovered.80,81,82,83 Non-genetic factors such as lifestyles, psychosocial factors, environment, and diseases related to AD (comorbidities and complications), may elevate the risk of developing AD. They may achieve this by altering biological pathways and genetic susceptibility,23,84,85,86 making it challenging to pinpoint a direct cause of clinical pathology in AD. Furthermore, different AD subtypes (typical and atypical) often exhibit various clinical symptoms.87,88,89 Thirdly, AD has multiple pathological features including Aβ plaques, NFTs, synaptic and neuronal loss, and neuroinflammation.90,91 Overall, the diversity of triggers, clinical manifestations, and neuropathological features underlie the heterogeneity of AD. Consequently, developing a comprehensive theoretical framework that links genetic foundations, molecular mechanisms, and clinical phenotypes of AD is extremely challenging. Current limitations in AD research also hinder our comprehensive understanding of its pathophysiology.1 Moreover, the high failure rate of clinical trials makes it difficult to effectively validate hypotheses, possibly attributed to the coexistence of multiple theories (which will be detailed in subsequent sections).

알츠하이머병의 메커니즘

알츠하이머병의 발병 기전을 밝히기 위해 수많은 가설이 제시되었지만, 알츠하이머병의 복잡한 특성으로 인해 통일된 이론은 여전히 찾기 어렵습니다.

AD는

가족성(AD 사례의 1~5% 차지)과 산발성(95% 이상)의

두 가지 주요 유형으로 분류할 수 있습니다.76

가족성 AD(FAD)는

주로 아밀로이드 전구체 단백질(APP), 프레세닐린 1(PS1), 프레세닐린 2(PS2) 유전자의

상 염색체 우성 유전 변이가 특징이며

일반적으로 30-65세 사이에 나타나고 빠르게 진행됩니다.

반면,

후기 발병 알츠하이머병이라고도 알려진 산발성 알츠하이머병(SAD)은

일반적으로 65세 이후에 나타나며

유전적 위험, 환경적 요인 및 다양한 동반 질환의 영향을 받습니다.77,78,79

전장유전체 연관성 연구(GWAS)와 전장유전체 메타 분석을 통해 면역 반응, 지질 대사, Aβ 플라크, NFT 및 세포 내 증식과 관련된 경로를 의미하는 SAD와 관련된 수많은 유전적 위험 유전자좌가 확인되었지만 아직 많은 유전자좌가 밝혀지지 않았습니다.80,81,82,83 생활 방식, 심리 사회적 요인, 환경 및 AD와 관련된 질병(동반 질환 및 합병증) 등 비 유전적 요인은 AD 발병 위험을 높일 수 있습니다. 이러한 요인들은 생물학적 경로와 유전적 감수성을 변화시킴으로써 이를 달성할 수 있으며,23,84,85,86 AD의 임상 병리의 직접적인 원인을 정확히 파악하기는 어렵습니다. 또한, AD 아형(전형적 및 비정형)에 따라 다양한 임상 증상이 나타나는 경우가 많습니다.87,88,89 셋째, AD는 Aβ 플라크, NFT, 시냅스 및 신경세포 손실, 신경염증을 포함한 여러 병리학적 특징을 가지고 있습니다.90,91 전반적으로 다양한 유발 요인, 임상 증상 및 신경 병리학적 특징이 AD의 이질성의 근간을 이루고 있습니다. 따라서 AD의 유전적 기초, 분자 메커니즘, 임상 표현형을 연결하는 포괄적인 이론적 틀을 개발하는 것은 매우 어려운 일입니다. 또한 현재 AD 연구의 한계는 병태생리에 대한 포괄적인 이해를 방해하고 있습니다.1 또한 임상시험의 높은 실패율로 인해 가설을 효과적으로 검증하기가 어려운데, 이는 여러 이론이 공존하기 때문일 수 있습니다(다음 섹션에서 자세히 설명할 예정임).

Cholinergic hypothesis

The cholinergic hypothesis was the earliest to delineate the pathogenesis of AD. It describes the severe damage of cholinergic neurons in the nucleus basalis of meynert (NBM), leading to a marked decrease in choline acetyltransferase (ChAT) activity within the primary projection areas - the cerebral cortex and hippocampus (regions associated with learning and memory). Additionally, this neuronal damage is accompanied by a significant increase in the density of senile plaques. The scenario in the cholinergic hypothesis suggests a close relationship between deficits of basal forebrain cholinergic and cognitive impairments observed in AD.91,92,93,94,95,96,97 Cholinergic neurons in the basal forebrain are crucial components of the central cholinergic system, significant contributing to the regulation of cognitive functions, attention, and memory.98 These cell bodies of neurons are predominantly located in the medial septal nucleus (MSN), diagonal band of broca (DBB), NBM, and substantia innominata (SI).97,99 It has been observed that cholinergic neurons in the NBM region are particularly susceptible to degeneration and loss in AD. It is believed to be associated with nerve growth factor (NGF)-dependent nutritional depletion.100,101 Acetylcholine (ACh) is synthesized from choline and acetyl-coenzyme A by ChAT, then transported into synaptic vesicles through the vesicular acetylcholine transporter (VAChT). When a neural signal arrives, ACh is released, where it binds to muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs) on the postsynaptic membrane to transmit neural signals. Subsequently, ACh in the synaptic cleft is degraded into choline by acetylcholinesterase (AChE) and reabsorbed into presynaptic cholinergic neurons.31,102,103,104 The decline in the activity of ChAT, combined with the detrimental effects of Aβ on nutritional imbalance, the synthesis, release, and degradation of ACh, leads to a reduction of ACh levels. This decrease impairs its physiological functions in learning, memory, motor regulation, and sleep cycle regulation.97,105,106,107,108 In summary, the cholinergic hypothesis, as a well-established and classic theory, has significantly advanced the early research and drug development for AD. AChE inhibitors (AChEIs), like donepezil (4), rivastigmine (5), and galantamine (6), which are approved over two decades ago, remain the mainstay of AD treatment in clinical management.109 Despite these advancements, the limited efficacy and side effects of such drugs, coupled with the presence of non-cholinergic groups in AD,99 and non-specificity in these pathological features,94 challenge the cholinergic hypothesis to fully explain the complex of AD pathology.

콜린성 가설

콜린성 가설은

알츠하이머병의 발병 기전을 가장 먼저 설명한 가설입니다.

이 가설은

마이너트 기저핵(NBM)의 콜린성 신경세포가 심각하게 손상되어

대뇌 피질과 해마(학습 및 기억과 관련된 영역)의 주요 투영 영역에서

콜린 아세틸전달효소(ChAT) 활동이 현저하게 감소하는 것을 설명합니다.

또한 이러한 신경세포 손상은 노인성 플라크 밀도의 현저한 증가를 동반합니다. 콜린성 가설의 시나리오는 기저 전뇌 콜린성 결핍과 알츠하이머에서 관찰되는 인지 장애 사이의 밀접한 관계를 시사합니다.91,92,93,94,95,96,97 기저 전뇌의 콜린성 뉴런은 중추 콜린성 시스템의 중요한 구성 요소이며 인지 기능, 주의력 및 기억 조절에 중요한 기여를 합니다.98 이러한 뉴런의 세포체는 주로 내측 중격핵(MSN), 브로카의 대각선 띠(DBB), NBM 및 실질핵(SI)에 위치합니다.97,99 NBM 영역의 콜린성 뉴런은 특히 AD에서 퇴화 및 손실에 취약한 것으로 관찰되었습니다. 이는 신경 성장 인자(NGF)에 의존하는 영양 고갈과 관련이 있는 것으로 여겨집니다.100,101 아세틸콜린(ACh)은 ChAT에 의해 콜린과 아세틸-코엔자임 A에서 합성된 다음 소포 아세틸콜린 수송체(VAChT)를 통해 시냅스 소포 내로 운반됩니다. 신경 신호가 도착하면 ACh가 방출되어 시냅스 후막의 무스카린 및 니코틴 아세틸콜린 수용체(mAChR 및 nAChR)와 결합하여 신경 신호를 전달합니다. 그 후 시냅스 틈새의 ACh는 아세틸콜린에스테라아제(AChE)에 의해 콜린으로 분해되어 시냅스 전 콜린성 뉴런으로 재흡수됩니다.31,102,103,104 ChAT의 활성 감소는 영양 불균형, ACh의 합성, 방출 및 분해에 대한 Aβ의 해로운 영향과 결합하여 ACh 수준의 감소로 이어집니다. 이러한 감소는 학습, 기억, 운동 조절 및 수면 주기 조절과 같은 생리적 기능을 손상시킵니다.97,105,106,107,108

요약하면,

콜린성 가설은 잘 정립된 고전적인 이론으로서

AD에 대한 초기 연구와 약물 개발을 크게 발전시켰습니다.

도네페질(4), 리바스티그민(5), 갈란타민(6)과 같이

20여 년 전에 승인된 AChE 억제제(AChEI)는

여전히 임상 관리에서 AD 치료의 주류를 이루고 있습니다.109

이러한 발전에도 불구하고 이러한 약물의 제한된 효능 및 부작용과 함께 AD에 비콜린성 그룹이 존재하고99 이러한 병리학적인 특징의 비특이성,94 복잡한 AD 병리를 완전히 설명하기에는 콜린성 가설에 도전이 되고 있습니다.

Amyloid hypothesis

The accumulation of Aβ is a hallmark pathological feature in both extensively studied autosomal dominant AD and sporadic late-onset AD patients.110 Aβ originates from the processing of the APP, a transmembrane glycoprotein, through its sequential cleavage by β-secretase and γ-secretase (a multiprotein complex with PS1 or PS2 as catalytic subunits). This process yields various lengths of Aβ fragments, with Aβ40 and Aβ42 being the predominant. The hydrophobic C-terminal of Aβ42 facilitates the β-sheet conformational transition and the aggregation and formation of the core component of senile plaques.78,111,112 Mutations in PS1, a typical mutation in FAD, potentially promote Aβ accumulation through multiple mechanisms, including increased Aβ production and impairment of autophagy functions.83,113,114,115 However, FAD mutations are not necessarily linked to an increase in Aβ42 levels or an elevation of Aβ42/Aβ40 ratio.78,116 The plaque formation in SAD is notably more intricate, related to a dynamic imbalance between Aβ production and clearance mechanisms.117 Apolipoprotein E (APOE), particularly the ε4 allele, stands out as the most crucial genetic risk factor for SAD. Carrying one or two APOE ε4 alleles increases the risk of AD by 2-3 and 12-fold, respectively.118 Research indicates that APOE protein is detectable in neuritic plaques, and individuals with the APOEε4 allele also have a higher burden of Aβ plaques in their brains,119,120 highlighting its critical influences on Aβ deposition. While the exact mechanisms remain to be agreed upon, both in vitro and in vivo experiments suggested several potential pathways for APOEε4, including enhancing Aβ production (promoting APP transcription and processing), facilitating Aβ aggregation (interaction with soluble and fibrillary Aβ aids in seeding/oligomerization/protofibril formation), and impairing Aβ clearance (disrupted glial and enzymatic Aβ degradation functions, and Aβ removal rate from the brain).121,122,123,124 Moreover, other genetic risk factors,125,126 cardiovascular health issues (such as diabetes, hypercholesterolemia), and lifestyle factors (such as diet and sleep)127 have also been extensively studied in recent years for their relationship with Aβ metabolism in SAD. The toxicity mechanism of Aβ aggregates remains uncertain, but different perspectives exist:77,128 Aβ might cause AD pathology through the loss of physiological functions during the aggregation process. Aβ monomers have neuroprotective properties, with assumed roles in antioxidant and antimicrobial activities, improving the condition of damaged nervous systems, regulating the vascular system, and enhancing synaptic plasticity.129,130 Soluble Aβ oligomers are the primary neurotoxic substances,131,132,133 disruption of cell membrane integrity,134 activation in inflammatory responses,135,136 causes of calcium homeostasis imbalance137 and mitochondrial dysfunction,138,139,140 triggers in oxidative stress,141 and damage factor of synapses.142 The potential downstream pathways of oligomers on neurons and glial cells are illustrated in Fig. 2 and Fig. 3. The amyloid cascade143 has been proposed for over 30 years, which provided crucial insights into the mechanisms of AD’s onset and progression.

This hypothesis has led to the development of drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, anti-amyloid antibodies, Aβ vaccine, and Aβ aggregation inhibitors, aimed at delaying the disease’s advancement. Currently, antibodies like aducanumab (1), lecanemab (2), and donanemab (10) show their promise in proving Aβ as a significant factor in AD development. However, in light of beneficial effects on reducing Aβ brain burden, the clinical value of these drugs remains to be validated.77,78 Of note, the amyloid cascade hypothesis remains controversial. This theory faces challenges in explaining the diverse pathological features, shows a weak correlation between Aβ and cognitive decline, and has failed to demonstrate efficacy in numerous clinical drugs to target Aβ.118,144,145,146,147 These findings suggest that Aβ deposition or plaque formation might not be the actual cause of the disease, but rather a result or secondary factor of the pathological process.77,148 Given the increasingly recognized critical role of tau, the pathological sequence and interplay of tau and Aβ in AD deserve further exploration.149,150,151

아밀로이드 가설

Aβ의 축적은 광범위하게 연구된 상염색체 우성 AD와 산발적인 후기 발병 AD 환자 모두에서 특징적인 병리학적인 특징입니다.110 Aβ는 막 통과 당단백질인 APP가 β-세크레타제 및 γ-세크레타제(PS1 또는 PS2를 촉매 하위 단위로 하는 다중 단백질 복합체)에 의해 순차적으로 절단되는 과정에서 발생합니다. 이 과정을 통해 다양한 길이의 Aβ 단편이 생성되며, Aβ40과 Aβ42가 가장 많이 생성됩니다. Aβ42의 소수성 C-말단은 β-시트 형태 전환과 노인성 플라크의 핵심 성분의 응집 및 형성을 촉진합니다.78,111,112 FAD의 전형적인 돌연변이인 PS1의 돌연변이는 Aβ 생성 증가 및 자가포식 기능 장애를 포함한 여러 메커니즘을 통해 Aβ 축적을 잠재적으로 촉진할 수 있습니다.83,113,114,115 그러나 FAD 돌연변이가 반드시 Aβ42 수준의 증가 또는 Aβ42/Aβ40 비율의 상승과 관련이 있는 것은 아닙니다.78,116 SAD의 플라크 형성은 Aβ 생산과 제거 메커니즘 사이의 동적 불균형과 관련하여 특히 더 복잡합니다.117 아포지단백 E(APOE), 특히 ε4 대립 유전자는 SAD의 가장 중요한 유전 위험 요인으로 부각되고 있습니다. 하나 또는 두 개의 APOE ε4 대립유전자를 보유하면 알츠하이머병의 위험이 각각 2-3배, 12배 증가합니다.118 연구에 따르면 APOE 단백질은 신경 플라크에서 검출되며 APOEε4 대립유전자를 가진 사람은 뇌에서 Aβ 플라크의 부담이 더 높으며,119,120 Aβ 침착에 중요한 영향을 미친다는 사실이 강조되고 있습니다. 정확한 메커니즘에 대해서는 아직 합의가 이루어지지 않았지만, 시험관 및 생체 내 실험에서 Aβ 생성 촉진(APP 전사 및 처리 촉진), Aβ 응집 촉진(시딩/올리고머화/프로섬유소 형성에서 수용성 및 섬유소 Aβ 보조제와의 상호작용), Aβ 제거 장애(신경교 및 효소 Aβ 분해 기능 장애, 뇌에서 Aβ 제거율) 등 APOEε4의 여러 잠재 경로를 제시했습니다. 121,122,123,124 또한, 다른 유전적 위험 요인,125,126 심혈관 건강 문제(당뇨병, 고콜레스테롤혈증 등), 생활습관 요인(식이 및 수면 등)127도 최근 몇 년간 SAD에서 Aβ 대사와의 관계에 대해 광범위하게 연구되고 있습니다. Aβ 응집체의 독성 메커니즘은 아직 불확실하지만 다양한 관점이 존재합니다.77,128 Aβ는 응집 과정에서 생리적 기능의 상실을 통해 AD 병리를 유발할 수 있습니다. Aβ 단량체는 항산화 및 항균 작용, 손상된 신경계 상태 개선, 혈관계 조절, 시냅스 가소성 향상 등의 역할을 하는 것으로 추정되는 신경 보호 특성을 가지고 있습니다.129,130 수용성 Aβ 올리고머는 주요 신경 독성 물질이며,131,132,133 세포막 완전성 파괴,134 염증 반응 활성화,135,136 칼슘 항상성 불균형137 및 미토콘드리아 기능 장애,138,139,140 산화 스트레스 유발,141 시냅스 손상 인자입니다.142 뉴런과 신경교세포에서 올리고머의 잠재적 다운스트림 경로는 그림 2와 그림 3 에 설명되어 있습니다. 아밀로이드 캐스케이드143는 30년 이상 제안되어 왔으며, 이는 알츠하이머 발병 및 진행 메커니즘에 대한 중요한 통찰력을 제공했습니다.

이 가설은

β-세크레타제 억제제,

γ-세크레타제 억제제 및 조절제,

항 아밀로이드 항체,

Aβ 백신,

Aβ 응집 억제제 등 질병의 진행을 지연시키기 위한 약물 개발로 이어졌습니다.

현재

아두카누맙(1), 레카네맙(2), 도나네맙(10)과 같은 항체는

Aβ가 AD 발병의 중요한 요인임을 입증하는 데 가능성을 보여주고 있습니다.

그러나 Aβ 뇌 부담 감소에 대한 유익한 효과를 고려할 때 이러한 약물의 임상적 가치는 아직 검증되지 않았습니다.77,78 아밀로이드 캐스케이드 가설은 여전히 논란의 여지가 있습니다. 이 이론은 다양한 병리학적 특징을 설명하는 데 어려움이 있고, Aβ와 인지 기능 저하 사이의 약한 상관관계를 보여주며, Aβ를 표적으로 하는 수많은 임상 약물에서 효능을 입증하지 못했습니다.118,144,145,146,147

이러한 결과는 Aβ 침착 또는 플라크 형성이 질병의 실제 원인이 아니라 병리학적 과정의 결과 또는 부차적 요인일 수 있음을 시사합니다.77,148 타우의 중요한 역할이 점차 인식되면서, AD에서 타우와 Aβ의 병리적 순서와 상호작용은 추가 연구가 필요한 상황입니다.149,150,151

Fig. 2

Schematic illustration depicting the possible molecular downstream pathways of Aβ on neuronal synapses and astrocytes. (1) Aβ is capable of interacting with cell membranes and binding to a variety of synaptic receptors such as PrPC, NMDA receptors, P75NTR, and mGluR5, which leads to a cascade of events including calcium dyshomeostasis, inhibition of long-term potentiation (LTP), tau hyperphosphorylation, mitochondrial dysfunction, and oxidative stress, ultimately resulting in neuronal death.112,632,633 (2) Aβ blocks the reuptake of glutamate by excitatory amino acid transporter (EAAT) receptors, causing glutamate accumulation intersynaptically and neuronal hyperactivity.634 (3) Aβ and some pro-inflammatory cytokines (such as TNFα, IL-1α, and C1q) may induce the A1 phenotype of astrocytes. This transformation may involve altering astrocyte functions and modulating their interactions with other cells (such as neurons and microglia), thereby participating in processes such as Aβ deposition, neuroinflammation, synaptic loss, and neuronal death.635,636,637 (4) APOE, primarily released from astrocytes, associates with lipoproteins to form APOE-associated lipoprotein particles, which can bind to soluble Aβ and mediate its clearance119

신경세포 시냅스와 성상교세포에서 Aβ의 가능한 분자 하류 경로를 보여주는 모식도.

(1) Aβ는 세포막과 상호 작용하여 PrPC, NMDA 수용체, P75NTR, mGluR5 등 다양한 시냅스 수용체와 결합할 수 있으며, 이는 칼슘 항상성 이상, 장기 강화(LTP) 억제, 타우 과인산화, 미토콘드리아 기능 장애, 산화 스트레스 등의 일련의 사건을 유발하여 궁극적으로 신경세포 사멸을 초래합니다.112,632,633

(2) Aβ는 흥분성 아미노산 수송체(EAAT) 수용체에 의한 글루타메이트 재흡수를 차단하여 시냅스 간 축적과 신경 과잉 활동을 유발합니다.634

(3) Aβ와 일부 전 염증성 사이토카인(TNFα, IL-1α, C1q 등)은 성상교세포의 A1 표현형을 유도할 수 있습니다. 이러한 변형은 성상세포 기능을 변화시키고 다른 세포(예: 뉴런 및 미세아교세포)와의 상호작용을 조절하여 Aβ 침착, 신경 염증, 시냅스 손실, 신경세포 사멸과 같은 과정에 관여할 수 있습니다.635,636,637

(4) 주로 성상세포에서 방출되는 APOE는 지질 단백질과 결합하여 APOE 관련 지질 단백질 입자를 형성하여 수용성 Aβ에 결합하고 그 제거를 매개할 수 있습니다119.

Fig. 3

Schematic illustration depicting potential molecular downstream pathways of Aβ on microglia. Microglia has numerous pattern recognition receptors that can bind to Aβ, initiating an inflammatory cascade. This process promotes the assembly and activation of NLRP3, leading to the release of pro-inflammatory cytokines, which further exacerbate the aggregation of Aβ.171 In addition, the diagram also encompasses the downstream signaling pathways of TREM2.638,639 Some variants associated with AD, such as the TREM2 variant R47H, may potentially diminish the binding or internalization of TREM2 with ligands such as APOE-Aβ complexes, APOE, phospholipids, and Aβ. This reduction may consequently impair the activation of microglial cells, thereby compromising their ability to clear amyloid plaques.638,640,641,642,643 It is worth noting that there remain many uncertainties and controversies regarding the in vivo ligands and signaling pathways of TREM2, as well as the relationship between TREM2 variants and AD. Future in vivo experiments are needed to elucidate these aspects

미세아교세포에서 Aβ의 잠재적인 분자 하류 경로를 나타내는 모식도.

미세아교세포에는 Aβ에 결합하여 염증성 캐스케이드를 시작할 수 있는 수많은 패턴 인식 수용체가 있습니다. 이 과정은 NLRP3의 조립과 활성화를 촉진하여 염증성 사이토카인의 방출로 이어지고, 이는 Aβ의 응집을 더욱 악화시킵니다.171 또한 이 다이어그램은 TREM2의 다운스트림 신호 경로도 포함합니다.638,639 TREM2 변이체 R47H와 같은 AD와 관련된 일부 변이체는 APOE-Aβ 복합체, APOE, 인지질, Aβ와 같은 리간드와 TREM2의 결합 또는 내부화를 잠재적으로 감소시킬 수 있습니다. 이러한 감소는 결과적으로 미세아교세포의 활성화를 저해하여 아밀로이드 플라크를 제거하는 능력을 손상시킬 수 있습니다.638,640,641,642,643 TREM2의 생체 내 리간드 및 신호 경로와 TREM2 변이체와 AD 간의 관계에 관한 많은 불확실성과 논란이 남아 있다는 점에 유의할 필요가 있습니다. 이러한 측면을 규명하기 위해서는 향후 생체 내 실험이 필요합니다.

Tau protein hypothesis

As a major component of NFTs, tau protein exhibits a spatial and temporal distribution that strongly correlates with clinical symptoms, making it a highly specific pathological biomarker in AD patients.152 Tau is a microtubule-associated protein predominantly expressed in the axons of neurons, with lower expression‎ levels in dendrites, soma, and glial cells.153,154 It hosts numerous phosphorylation sites across its N-terminal region, C-terminal region, and repeat region, which are regulated by a balance of various kinases and phosphatases to maintain normal neuronal physiological functions.150,155 Under pathological conditions, an imbalanced activity of phosphatases and kinases leads to hyperphosphorylation of tau.156,157 This process leads to the detachment of tau protein from microtubules, followed by conformational changes and mislocalization, accumulation of tau oligomers, paired helical filaments (PHFs), and NFTs within the cell body and dendrites. These changes ultimately impair neuronal function and cause cell death.158,159,160 Additionally, other post-translational modifications, including truncation,161,162 glycosylation,163 glycation,164 and sumoylation,165 play an active role in promoting tau aggregation and increasing its toxicity. Tau oligomers not only generate neurotoxicity within cells but also facilitate pathological spread through synaptic transmission. This process induces the aggregation of monomeric tau in recipient neurons, leading to the formation of new oligomers.166 Overall, the significance of tau in AD pathogenesis stems from the strong correlation between tau accumulation and cognitive symptoms.152 In recent years, there has been a heightened focus on tau deposition, including the correlation between tau deposition, brain atrophy, and glucose metabolism in both typical and atypical AD,167,168 as well as the effects of tau deposition at the molecular and cellular levels.169 Despite initial investigations into drugs based on the tau hypothesis not yielding promising results,152 numerous treatments are still actively being developed. These include kinase inhibitors, tau aggregation inhibitors, tau immunotherapies, antisense oligonucleotides that inhibit tau production, agents that promote autophagy-mediated degradation, and tau-targeted PROTACs.166,170

타우 단백질 가설

타우 단백질은

NFT의 주요 구성 요소로서

임상 증상과 밀접한 상관관계가 있는 공간적, 시간적 분포를 보여

AD 환자에서 매우 특이적인 병리학적 바이오마커가 됩니다.152

타우는 신경세포의 축삭에서 주로 발현되는

미세소관 관련 단백질로

수상돌기, 소마 및 신경교세포에서는 발현 수준이 낮습니다.153,154

N-말단 영역, C-말단 영역 및 반복 영역에 걸쳐 수많은 인산화 부위를 호스트하며, 이는 정상적인 신경세포 생리 기능을 유지하기 위해 다양한 키나아제와 포스파타제의 균형에 의해 조절됩니다.150,155 병리학적인 조건에서 포스파타제와 키나아제의 활성 불균형은 타우의 과인산화를 초래합니다.156,157 이 과정에서 타우 단백질이 미세소관에서 분리되고 세포체와 수상돌기 내에 타우 올리고머, 쌍 나선 필라멘트(PHF), NFT가 축적되어 형태 변화와 위치가 잘못 지정됩니다. 이러한 변화는 궁극적으로 신경세포 기능을 손상시키고 세포 사멸을 유발합니다.158,159,160 또한 절단,161,162 글리코실화,163 당화,164 및 수모일화,165를 포함한 다른 번역 후 변형은 타우 응집을 촉진하고 독성을 증가시키는 데 적극적인 역할을 합니다. 타우 올리고머는 세포 내에서 신경 독성을 생성할 뿐만 아니라 시냅스 전달을 통해 병리학적 확산을 촉진합니다. 이 과정은 수용 뉴런에서 단량체 타우의 응집을 유도하여 새로운 올리고머를 형성합니다.166 전반적으로, 타우 축적과 인지 증상 사이의 강한 상관관계에서 알츠하이머 병인에서 타우의 중요성이 부각됩니다.152 최근 몇 년 동안 타우 침착에 대한 관심이 높아져, 전형적 및 비정형 AD 모두에서 타우 침착, 뇌 위축, 포도당 대사 사이의 상관관계,167,168 분자 및 세포 수준에서의 타우 침착의 효과에 대한 연구가 활발히 진행되고 있습니다.169

타우 가설에 기반한 약물에 대한

초기 조사에서 유망한 결과를 얻지는 못했지만,152

수많은 치료법이 여전히 활발히 개발되고 있습니다.

여기에는

키나아제 억제제,

타우 응집 억제제,

타우 면역 요법,

타우 생성을 억제하는 안티센스 올리고뉴클레오티드,

자가포식 매개 분해를 촉진하는 약제,

타우 표적 PROTAC 등이 포함됩니다.166,170

Neuroinflammation hypothesis

Neuroinflammation is generally characterized as a chronic inflammatory response in the central nervous system (CNS) that fails to resolve on its own. It often involves the activation of glial cells and the release of pro-inflammatory factors during neuroinflammation.171 Microglia, the CNS foremost innate immune cells, acts as an initial defense against danger-associated molecular patterns and pathogen-associated molecular pattern receptors. Microglia are elongated, branched cells that monitor their environment and secrete neurotrophic factors in a state of homeostasis. Once stimulation is detected, microglia undergo morphological changes and initiate a variety of responses.172,173 Aβ is a typical trigger for microglial activation. Activated microglia migrate towards senile plaques, engulf Aβ, and release enzymes to break down Aβ. Over prolonged periods, they might become less efficient at handling Aβ but continue to generate proinflammatory cytokines.174,175 Aβ also causes the formation and activation of the NLRP3 inflammasome within microglia, which releases ASC specks that bind rapidly to Aβ in promoting Aβ aggregates and the spread of Aβ pathology.176 Interactions between microglia and tau protein in the later stages of AD may contribute to increased tau phosphorylation and exosomal tau secretion, thereby promoting the spread of tau.177,178 With the exaggerated activation, the complement cascade potentially leads to aberrant synapse pruning by microglia, further exacerbating AD pathology.171 Researchers have identified different activation stages of microglia, each associated with distinct gene expression‎ patterns. Initial stages were characterized by genes related to cell proliferation, whereas later stages feature genes linked to immune responses.171 GWAS have pinpointed numerous risk genes closely linked to microglial activities, highlighting the significance of microglia as a promising therapeutic target.179 

Targeting triggering receptor expressed on myeloid cells 2 (TREM2) has the potential to harness neuroprotective properties by elevating microglial responsiveness to pathological proteins.180 Meanwhile, APOE4 could modify the behavior and function of activated microglia, contributing to increased Aβ deposition, tau-associated neurodegeneration, enhanced inflammation, altered immune responses, and disrupted synaptic homeostasis.123,181,182,183,184 Consequently, diminishing APOE4 expression‎ in Aβ plaque-associated microglia may offer an effective approach. In summary, neuroinflammation is intricately associated with Aβ and tau pathologies, and the discovery of numerous immune response-related risk factors indicates that neuroinflammation is a significant factor in AD pathogenesis. Recent investigations have also expanded the scope of AD-related inflammation, exploring how the gut microbiota, oral microbiome, and viruses such as herpesviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impact neuroinflammation.185,186,187 Regarding anti-inflammatory therapies, the effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs) remains inconclusive.188,189 Despite this, the primary focuses in the development of anti-inflammatory drugs are appropriate intervention timing and enhancing target specificity.171,190 Currently, numerous drugs targeting inflammation-related receptors, signaling pathways, and pro-inflammatory cytokines are under clinical trials.185

신경염증 가설

신경염증은

일반적으로 중추신경계(CNS)에서 저절로 해결되지 않는

만성 염증 반응으로 특징지어집니다.

신경염증은

종종 신경교세포의 활성화와 전염증 인자의 방출을 수반합니다.171

CNS의 가장 중요한 선천성 면역 세포인

미세아교세포는

위험 관련 분자 패턴과 병원체 관련 분자 패턴 수용체에 대한 초기 방어 역할을 합니다.

미세아교세포는 길쭉하고 가지가 있는 세포로,

항상성 상태에서 환경을 모니터링하고

신경 영양 인자를 분비합니다.

자극이 감지되면 미세아교세포는

형태적 변화를 겪으며 다양한 반응을 시작합니다.172,173

Aβ는

미세아교세포 활성화를 위한

대표적인 트리거입니다.

활성화된 미세아교세포는

노인성 플라크 쪽으로 이동하여 Aβ를 집어삼키고

Aβ를 분해하는 효소를 방출합니다.

장기간에 걸쳐 Aβ를 처리하는 효율성은 떨어지지만

염증성 사이토카인을 계속 생성할 수 있습니다.174,175

또한

Aβ는 미세아교세포 내에서 NLRP3 인플라마좀의 형성 및 활성화를 유발하여

Aβ에 빠르게 결합하여 Aβ 응집체와 Aβ 병리의 확산을 촉진하는

ASC 얼룩을 방출합니다.176

AD 후기 단계에서

미세아교세포와 타우 단백질 간의 상호작용은

타우 인산화와 엑소좀 타우 분비를 증가시켜 타우의 확산을 촉진할 수 있습니다.177,178

활성화가 과장되면 보체 캐스케이드가 미세아교세포에 의한 비정상적인 시냅스 가지치기를 유발하여 AD 병리를 더욱 악화시킬 가능성이 있습니다.171 연구자들은 각각 다른 유전자 발현 패턴과 관련된 미세아교세포의 활성화 단계를 확인했습니다. 초기 단계는 세포 증식과 관련된 유전자가 특징인 반면, 후기 단계는 면역 반응과 관련된 유전자가 특징입니다.171 GWAS는 미세아교세포 활동과 밀접하게 연결된 수많은 위험 유전자를 찾아내어 유망한 치료 표적으로서 미세아교세포의 중요성을 부각시켰습니다.179

골수성 세포 2(TREM2)에서 발현되는 트리거링 수용체를 표적으로 삼으면 병리학적 단백질에 대한 미세아교세포의 반응성을 높여 신경 보호 특성을 활용할 수 있는 잠재력이 있습니다.180 한편, APOE4는 활성화된 미세아교세포의 행동과 기능을 수정하여 Aβ 침착 증가, 타우 관련 신경 퇴화, 염증 강화, 면역 반응 변화, 시냅스 항상성 파괴에 기여할 수 있습니다.123,181,182,183,184 결과적으로 Aβ 플라크 관련 미세아교세포에서 APOE4 발현 감소는 효과적인 접근 방식을 제공할 수 있습니다. 요약하면, 신경염증은 Aβ 및 타우 병리와 복잡하게 연관되어 있으며, 수많은 면역 반응 관련 위험 인자의 발견은 신경염증이 AD 발병의 중요한 인자임을 나타냅니다.

최근 연구에서는 장내 미생물, 구강 미생물, 헤르페스 바이러스 및 중증 급성 호흡기 증후군 코로나바이러스 2(SARS-CoV-2)와 같은 바이러스가 신경염증에 미치는 영향을 탐구하면서 AD 관련 염증의 범위를 확장했습니다.185,186,187 항염증 치료와 관련하여 비스테로이드 항염증제(NSAID)의 효과는 아직 결정적이지 않습니다.188,189 그럼에도 불구하고 항염증제 개발의 주요 초점은 적절한 개입 시기와 표적 특이성 향상입니다.171,190 현재 염증 관련 수용체, 신호 경로 및 전 염증성 사이토카인을 표적으로 하는 수많은 약물들이 임상 시험 중입니다.185

Oxidative stress hypothesis

During regular metabolic processes, the body produces reactive oxygen species (ROS), reactive nitrogen species, and other highly reactive and unstable substances. These substances are generally kept at low levels by an efficient antioxidant defense system to protect cells from oxidative damage.191,192 However, in the brain of AD patients, factors such as metal accumulation, overexpression‎ of related enzymes (e.g., NADPH oxidase), and mitochondrial dysfunction are involved in producing excessive ROS, surpassing the ability of the endogenous antioxidant system and resulting in an oxidative imbalance. It will damage neuronal membrane lipids, proteins, and nucleic acids, ultimately causing neuronal cell death.191,193,194,195 The abnormality of the electron transport chain within mitochondria is particularly a significant contributor to free radical production. Aβ plays a crucial role in mitochondrial dysfunction by reducing the activities of key enzymes and disrupting the dynamics of mitochondria.192,196 Oxidative stress presented in the early stages of AD acts as a crosstalk between different hypotheses of AD.197 For example, oxidative stress modulates the process of APP and the activity of secretases, thereby promoting the amyloid pathway. Furthermore, it is instrumental in the phosphorylation of tau proteins and the subsequent formation of NFTs. The activation of microglia induced by ROS triggers a neuroinflammatory cycle. The presence of free metals and complexes of Aβ with metals act as catalysts for ROS production, ultimately leading to neuronal cell death.195 Given these connections between oxidative stress and other AD mechanisms, antioxidants have emerged as promising agents in AD treatment with positive outcomes observed in animal models.198 However, the efficacy of antioxidants in clinical trials for AD remains uncertain. Several studies have indicated that standalone treatments or treatments in combination with cholinesterase inhibitors did not confer significant cognitive benefits to patients with AD. Future efforts should focus on optimizing drug dosages and initiating antioxidant therapy early in the course of the disease’s progression for potentially improved outcomes.199 In summary, oxidative stress has garnered widespread attention as a significant factor in the pathogenesis of AD. Nevertheless, the interplay between Aβ and oxidative stress,200 as well as their sequence within AD,201,202 require further research and exploration.

산화 스트레스 가설

정상적인 대사 과정에서 신체는 활성 산소종(ROS), 반응성 질소종 및 기타 반응성이 높고 불안정한 물질을 생성합니다. 이러한 물질은 일반적으로 효율적인 항산화 방어 시스템에 의해 낮은 수준으로 유지되어 산화적 손상으로부터 세포를 보호합니다.191,192 그러나 알츠하이머병 환자의 뇌에서는 금속 축적, 관련 효소(예: NADPH 산화 효소)의 과발현, 미토콘드리아 기능 장애와 같은 요인들이 내인성 항산화 시스템의 능력을 초과하여 과도한 ROS를 생성하고 산화 불균형을 초래하는 데 관여합니다. 이는 신경 세포막 지질, 단백질 및 핵산을 손상시켜 궁극적으로 신경 세포 사멸을 유발합니다.191,193,194,195 미토콘드리아 내 전자 수송 사슬의 이상은 특히 활성 산소 생성에 중요한 기여를 합니다. Aβ는 주요 효소의 활동을 감소시키고 미토콘드리아의 역학을 방해함으로써 미토콘드리아 기능 장애에 중요한 역할을 합니다.192,196 AD의 초기 단계에서 나타나는 산화 스트레스는 AD의 여러 가설 사이의 교차점 역할을 합니다.197 예를 들어 산화 스트레스는 아밀로이드 경로를 촉진하여 APP의 과정과 분비 효소의 활성을 조절하는 역할을 합니다. 또한 타우 단백질의 인산화와 그에 따른 NFT의 형성에 중요한 역할을 합니다. ROS에 의해 유도된 미세아교세포의 활성화는 신경염증 주기를 촉발합니다. 유리 금속과 금속과 Aβ의 복합체는 ROS 생성의 촉매 역할을 하여 궁극적으로 신경 세포 사멸로 이어집니다.195 산화 스트레스와 다른 AD 메커니즘 사이의 이러한 연관성을 고려할 때, 항산화제는 동물 모델에서 긍정적인 결과가 관찰되면서 AD 치료에서 유망한 약제로 부상했습니다.198 그러나 AD 임상 시험에서 항산화제의 효능은 여전히 불확실합니다. 여러 연구에 따르면 항산화제 단독 치료 또는 콜린에스테라아제 억제제와의 병용 치료는 AD 환자에게 유의미한 인지적 이점을 제공하지 않는 것으로 나타났습니다. 향후의 노력은 잠재적으로 개선된 결과를 위해 약물 용량을 최적화하고 질병 진행 초기에 항산화 치료를 시작하는 데 초점을 맞춰야 합니다.199 요약하면, 산화 스트레스는 알츠하이머병 발병의 중요한 요인으로 널리 주목을 받고 있습니다. 그럼에도 불구하고 Aβ와 산화 스트레스 사이의 상호 작용,200 및 AD 내에서 이들의 순서,201,202는 더 많은 연구와 탐구가 필요합니다.

Metal ion hypothesis

In physiological conditions, trace metals maintain homeostasis of the neuronal metal ion microenvironment. This balance can be disrupted by the inappropriate deposition or misdistribution of metal ions, with the dyshomeostasis of Fe2+, Cu2+, and Zn2+ closely associated with AD.203 The accumulation of these biometals in Aβ plaques and NFTs plays a critical role in pathological protein deposition. For instance, they may modulate the activity of essential enzymes, alter the conformation of proteins, or disrupt clearing pathways.203,204,205 When metals are sequestered in protein deposits, it may initiate a cascade of ROS production and accentuate toxicity.206 Specifically, iron-induced oxidative stress causes increased release of iron from iron-containing proteins, converting Fe3+ to Fe2+ intracellularly. Fe2+ overload can induce ferroptosis and lipid peroxidation through the generation of ROS via the Fenton reaction, ultimately resulting in neuronal death. Similarly, Cu+ directly binds to lipoylated dihydrolipoyl transacetylase (DLAT), inducing lipoylated DLAT aggregation and ultimately leading to cuproptosis.203 The sequestration in protein deposits also causes functional metal loss, potentially contributing to the cognitive decline in AD. Zinc could interfere with signaling through N-methyl-D-aspartate (NMDA) receptors. Supplementation of zinc may promote the maturation of proBNDF, reducing synaptic dysfunction and neuronal death.204,205 Hence, zinc deficiency is crucial in the context of glutamate excitotoxicity and synaptic dysfunction in AD. Overall, metal dyshomeostasis is closely linked to various events in AD such as amyloidosis, tauopathy, oxidative stress, and neuronal death. This hypothesis provides an alternative approach to understanding the pathogenesis of AD and detecting pathological changes. Further research is necessary to elucidate its role in AD. Additionally, metal ion chelators, developed based on this hypothesis, need to overcome challenges such as adverse events and poor blood-brain barrier (BBB) permeability to demonstrate their potential therapeutic value.203

금속 이온 가설

생리적 조건에서 미량 금속은 신경세포의 금속 이온 미세 환경의 항상성을 유지합니다. 이러한 균형은 금속 이온의 부적절한 침착 또는 잘못된 분포로 인해 깨질 수 있으며, Fe2+, Cu2+, Zn2+의 항상성 장애는 알츠하이머병과 밀접한 관련이 있습니다.203 Aβ 플라크와 NFT에 이러한 생체 금속이 축적되면 병적인 단백질 침착에 중요한 역할을 합니다.

예를 들어, 필수 효소의 활성을 조절하거나 단백질의 형태를 변경하거나 제거 경로를 방해할 수 있습니다.203,204,205 금속이 단백질 침착물에 격리되면 일련의 ROS 생성을 시작하고 독성을 강조할 수 있습니다.206

특히 철에 의한 산화 스트레스는

철 함유 단백질에서 철 방출을 증가시켜

세포 내에서 Fe3+를 Fe2+로 전환시킵니다.

Fe2+ 과부하는 펜톤 반응을 통한 ROS 생성을 통해

철분과산화 및 지질 과산화를 유도하여 궁극적으로

신경세포 사멸을 초래할 수 있습니다.

마찬가지로

Cu+는 리포화 디하이드로리포일 트랜스아세틸화 효소(DLAT)에 직접 결합하여

리포화 DLAT 응집을 유도하고 궁극적으로 쿠프롭토시스를 유발합니다.203

단백질 침착물의 격리는 또한 기능성 금속 손실을 유발하여 잠재적으로 AD의 인지 기능 저하에 기여합니다.

아연은

N-메틸-D-아스파르트산염(NMDA) 수용체를 통한 신호 전달을 방해할 수 있습니다.

아연을 보충하면 proBNDF의 성숙을 촉진하여

시냅스 기능 장애와 신경세포 사멸을 줄일 수 있습니다.204,205

따라서

아연 결핍은

AD의 글루타메이트 흥분 독성과 시냅스 기능 장애의 맥락에서 매우 중요합니다.

전반적으로 금속 항상성 이상은

아밀로이드증, 타우 병증, 산화 스트레스 및 신경 세포 사멸과 같은

다양한 AD의 현상과 밀접한 관련이 있습니다.

이 가설은 알츠하이머병의 발병 기전을 이해하고 병리학적 변화를 감지하기 위한 대안적인 접근 방식을 제공합니다. 알츠하이머병에서의 역할을 규명하기 위해서는 추가 연구가 필요합니다. 또한 이 가설을 바탕으로 개발된 금속 이온 킬레이트는 부작용과 낮은 혈액뇌장벽(BBB) 투과성 등의 문제를 극복해야 잠재적 치료 가치를 입증할 수 있습니다.203

Glutamatergic excitotoxicity

Glutamate is the main excitatory neurotransmitter of glutamatergic neurotransmission in the CNS.206 Their receptors comprise ionotropic glutamate receptors, including NMDA receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and kainate receptors, as well as metabotropic glutamate (mGlu) receptors.207 Glutamate mainly interacts with NMDA receptors to control the influx of sodium and calcium to neurons. Magnesium ions act to shut the NMDA receptor’s cationic channel and block the entry of ions into neurons under physiological conditions. However, in AD, there is an overstimulation of NMDA receptors, which results in the dislodgement of magnesium and permits an excessive entry of sodium and calcium ions.208,209 The entry of sodium into neurons causes their temporary swelling, while an increase in calcium levels initiates various Ca2+-dependent processes. These processes include the creation of ROS, disruption of mitochondrial function, and the activation of necrotic/apoptotic pathways, ultimately resulting in permanent excitotoxic damage to the neurons.210,211 Overall, pharmaceutical validation of the glutamatergic excitotoxicity hypothesis demonstrates the effectiveness of neurotransmitter regulation in improving cognitive symptoms. However, the limitations of neurotransmitter-based medications and the focus on other hypotheses appear to hinder further investigation into the mechanisms of excitotoxicity. The observed changes in the inhibitory neurotransmitter system, exemplified by γ-aminobutyric acid,212 and the potential for excitotoxicity to alter cognitive levels earlier than Aβ and tau pathologies,209 suggest that excitotoxicity might hold greater potential in AD treatment.

글루타메이트 흥분성 독성

글루타메이트는 중추신경계의 주요 흥분성 신경 전달 물질입니다.206 글루타메이트 수용체는 NMDA 수용체, α-아미노-3-하이드록시-5-메틸-4-이소사졸 프로피온산(AMPA) 수용체, 카이나테 수용체를 포함한 이온성 글루타메이트 수용체와 대사성 글루타메이트(mGlu) 수용체로 구성됩니다.207

글루타메이트는 주로 NMDA 수용체와 상호작용하여

나트륨과 칼슘이 뉴런으로 유입되는 것을 조절합니다.

마그네슘 이온은 생리적 조건에서 NMDA 수용체의 양이온 채널을 닫고 이온이 뉴런으로 유입되는 것을 차단하는 역할을 합니다. 그러나 알츠하이머병에서는 NMDA 수용체가 과도하게 자극되어 마그네슘이 제거되고 나트륨과 칼슘 이온이 과도하게 유입됩니다.208,209 나트륨이 신경세포로 유입되면 일시적으로 부종이 일어나고 칼슘 수치가 증가하면 다양한 Ca2+ 의존적 과정이 시작됩니다.

이러한 과정에는

ROS 생성, 미토콘드리아 기능 장애, 괴사/사멸 경로의 활성화가 포함되어

궁극적으로 신경세포에 영구적인 흥분성 손상을 초래합니다.210,211

전반적으로 글루탐산 흥분성 가설의 약학적 검증은 인지 증상 개선에 신경전달물질 조절의 효과가 있음을 입증합니다. 그러나 신경전달물질 기반 약물의 한계와 다른 가설에 대한 집중은 흥분성 독성의 메커니즘에 대한 추가 연구를 방해하는 것으로 보입니다.

γ-아미노부티르산으로 대표되는 억제성 신경전달물질 시스템의 변화,212

그리고 흥분성 독성이 Aβ 및 타우 병리보다 인지 수준을

더 일찍 변화시킬 수 있는 가능성,209은

흥분성 독성이 AD 치료에서 더 큰 잠재력을 가질 수 있음을 시사합니다.

Microbiota-gut-brain axis hypothesis

In recent years, the microbiota-gut-brain axis hypothesis has attracted significant attention, unveiling potential pathways for novel therapeutic strategies.213 The microbiota predominantly consists of bacteria, with smaller populations of fungi, viruses, archaea, and protozoa. These microorganisms offer trophic and protective effects in metabolism and innate immunity and influence brain function via the gut-microbiota-brain axis.214,215,216 The microbiota-gut-brain axis refers to a bidirectional communication system between the gut and the brain, including metabolic, endocrine, neural, and immune pathways that can work independently or in concert.213,216 Alterations in the host’s diet, use of antibiotics, exposure to psychosocial stress, or irregularities in the immune system may shift the relative proportions of bacterial species, resulting in a disruption of the microbiota’s composition and functionality as dysbiosis.214 Subsequently, the intestinal epithelial barrier is compromised. Harmful substances and microorganisms in the intestinal tract could enter the bloodstream, triggering an immune response that may lead to systemic inflammation. The onset of systemic inflammation may allow inflammatory mediators to cross over the BBB and impact microglia, further exacerbating neuroinflammation.213,217 This process is accompanied by imbalanced neurotransmission,218 which ultimately leads to neuronal degeneration and damage. Overall, the microbiota-gut-brain axis hypothesis establishes a connection between the peripheral immune system and the CNS, offering a fresh perspective for AD research. Moreover, drugs and biomarkers219 related to the gut microbiome are potentially considered. However, the investigation of this mechanism is still in an early stage. The exact mechanisms by which the gut microbiome affects brain activity or its connections with other pathological features of AD remain unclear.

미생물-장-뇌 축 가설

최근 미생물총-장-뇌 축 가설은 새로운 치료 전략의 잠재적 경로를 밝히면서 큰 주목을 받고 있습니다.213 미생물총은 주로 박테리아로 구성되며 곰팡이, 바이러스, 고세균 및 원생동물은 소량으로 존재합니다. 이러한 미생물은 신진대사와 선천 면역에 영양 및 보호 효과를 제공하며 장내 미생물-뇌 축을 통해 뇌 기능에 영향을 줍니다.214,215,216 미생물-장-뇌 축은 장과 뇌 사이의 양방향 통신 시스템을 의미하며, 대사, 내분비, 신경 및 면역 경로가 독립적으로 또는 함께 작용할 수 있습니다.213,216 숙주의 식단 변화, 항생제 사용, 심리사회적 스트레스 노출 또는 면역 체계의 이상은 박테리아 종의 상대적 비율을 변화시켜 미생물총의 구성과 기능에 장애를 초래하는 이상균총증으로 이어질 수 있습니다.214 결과적으로 장 상피 장벽이 손상됩니다.

장내 유해 물질과 미생물이 혈류로 유입되어

전신 염증을 유발할 수 있는 면역 반응을 일으킬 수 있습니다.

전신 염증이 시작되면 염증 매개체가 BBB를 통과하여

미세아교세포에 영향을 미쳐 신경 염증을 더욱 악화시킬 수 있습니다.213,217

이 과정은 불균형한 신경 전달을 동반하며,218 궁극적으로 신경세포 퇴화와 손상으로 이어집니다. 전반적으로 미생물-장-뇌 축 가설은 말초 면역계와 중추신경계 사이의 연관성을 입증하여 알츠하이머병 연구에 새로운 관점을 제시합니다. 또한 장내 미생물과 관련된 약물 및 바이오마커219가 잠재적으로 고려될 수 있습니다. 그러나 이 메커니즘에 대한 연구는 아직 초기 단계에 머물러 있습니다. 장내 미생물이 뇌 활동에 영향을 미치는 정확한 메커니즘이나 AD의 다른 병리학적 특징과의 연관성은 아직 명확하지 않습니다.

Abnormal autophagy

Autophagy, a highly conserved metabolic degradation process, maintains cellular homeostasis by delivering intracellular protein aggregates and damaged organelles to lysosomes for degradation and recycling.220,221 It primarily occurs via three types: microautophagy, chaperone-mediated autophagy, and macroautophagy (commonly referred to as autophagy).222 Microautophagy is the simplest pathway in which cytoplasmic substrates enter vesicles formed by morphological changes in lysosomal or endosomal membranes, and are ultimately degraded within the lysosome.220,223,224 Chaperone-mediated autophagy involves chaperone proteins recognizing and binding to specific protein sequences (KFERQ-like motifs), facilitating substrate transfer to lysosomes through interactions with lysosomal membrane proteins (LAMP2A).224,225,226 Macroautophagy, the main subtype, is primarily regulated by mTORC1 for activating the unc-51-like autophagy activating kinase 1 (ULK1) complex and dephosphorylating transcription factor EB (TFEB) to induce autophagy. Under the regulation of autophagy-related protein complexes, a phagophore forms and gradually expands to a sealed autophagosome. The autophagosomes then move retrogradely along microtubules to the microtubule organizing center, which is rich in lysosomes. They fuse with lysosomes to form autolysosomes, where substrate degradation occurs. In certain instances, autophagosomes could first merge with endosomes to form amphisomes, which then fuse with lysosomes.222,224,227,228,229 

However, the abundant accumulation of autophagic vacuoles in swollen (malnourished) neurons is observed to have a linkage with Aβ/APP-βCTF, suggesting that autophagy clearance is severely disrupted under pathological conditions and is closely linked to amyloid pathology.115,225,230 This makes autophagy a focal point in recent AD pathogenesis research. There is increasing evidence indicating that genetic factors, reduced expression‎ of related proteins, and defective vesicular transportation are potential causes of autophagy pathway disruptions. These disruptions interfere with clearance mechanisms involving substrate engulfment, autophagosome formation, autophagosome-lysosome fusion, and lysosomal structure and function.227,229 In AD, autophagy defects mediate the disruption of protein homeostasis networks (production and extracellular secretion of Aβ, abnormal aggregation of tau protein) and lead to the accumulation of damaged organelles, such as dysfunctional mitochondria.231 In summary, abnormalities of autophagy are intimately related to the onset and progression of AD. There is a growing emphasis on the involvement of chaperone-mediated autophagy,232 contributions of glial cell autophagy,233,234 and the precise causes of mitochondrial autophagy disorders.235 Autophagy-stimulating drugs including small molecule therapies and gene therapies, have shown significant neuroprotective potential in various AD animal models, suggesting a potential intervention option.220,222,231,236,237 However, the challenges posed by the broad targets of autophagy modulators, and lack of appropriate in vivo autophagic flux detection methods, hinder further clinical applications of these drugs.222,227

비정상적인 자가포식

고도로 보존된 대사 분해 과정인 자가포식은

세포 내 단백질 응집체와 손상된 소기관을 분해 및 재활용을 위해

리소좀으로 전달하여 세포 항상성을 유지합니다.220,221

주로

미세 자가포식,

샤페론 매개 자가포식,

거대 자가포식(일반적으로 자가포식이라고 함)의 세 가지 유형을 통해 발생합니다.222

미세 자가포식은

세포질 기질이 리소좀 또는 엔도솜 막의 형태학적 변화에 의해 형성되는 소포에 들어가

궁극적으로 리소좀 내에서 분해되는 가장 단순한 경로입니다.220,223,224

샤페론 매개 자가포식은

샤페론 단백질이 특정 단백질 서열(KFERQ 유사 모티프)을 인식하고 결합하여

리소좀 막 단백질(LAMP2A)과 상호작용을 통해 리소좀으로 기질 이동을 촉진하는 것을 포함합니다. 224,225,226

주요 하위 유형인 매크로 오토파지는

주로 mTORC1에 의해 조절되어 unc-51 유사 오토파지 활성화 키나아제 1(ULK1) 복합체와 탈인산화 전사인자 EB(TFEB)를 활성화하여 오토파지를 유도합니다.

자가포식 관련 단백질 복합체의 조절에 따라

식세포가 형성되고 점차 봉인된 오토파지솜으로 확장됩니다.

그런 다음 오토파지솜은 미세소관을 따라 리소좀이 풍부한 미세소관 조직 센터로 역행적으로 이동합니다. 이들은 리소좀과 융합하여 오토리소좀을 형성하고, 여기서 기질 분해가 일어납니다. 경우에 따라 오토파지좀은 먼저 엔도솜과 합쳐져 암피좀을 형성한 다음 리소좀과 융합할 수 있습니다.222,224,227,228,229

그러나

부은(영양실조) 뉴런에서 자가포식 액포가 풍부하게 축적되는 것은

Aβ/APP-βCTF와 연관성이 있는 것으로 관찰되어

병리학적인 조건에서 자가포식 제거가 심각하게 중단되고

아밀로이드 병리와 밀접한 관련이 있음을 시사합니다.115,225,230

이것은

최근 AD 발병 연구에서

자가포식이 초점이 되고 있는 이유입니다.

유전적 요인, 관련 단백질의 발현 감소, 소포 수송 결함 등이

자가포식 경로 장애의 잠재적 원인이라는 증거가 점점 더 많아지고 있습니다.

이러한 장애는

기질 포집, 자가포식체 형성, 자가포식체-리소좀 융합,

리소좀 구조 및 기능과 관련된 제거 메커니즘을 방해합니다.227,229

AD에서 자가포식 결함은

단백질 항상성 네트워크의 파괴(Aβ의 생성 및 세포 외 분비, 타우 단백질의 비정상적인 응집)를 매개하고

기능 장애 미토콘드리아와 같은 손상된 소기관의 축적을 초래합니다.231

요약하면,

자가포식의 이상은

AD의 발병 및 진행과 밀접한 관련이 있습니다.

샤프론 매개 자가포식의 관여,232 아교세포 자가포식의 기여,233,234 그리고 미토콘드리아 자가포식 장애의 정확한 원인에 대한 관심이 높아지고 있습니다.235 저분자 요법 및 유전자 요법을 포함한 자가포식 자극 약물은 다양한 AD 동물 모델에서 상당한 신경 보호 가능성을 보여주며 잠재적인 개입 옵션을 제시하고 있습니다.220,222,231,236,237 그러나 자가포식 조절제의 광범위한 표적과 적절한 생체 내 자가포식 플럭스 검출 방법의 부족으로 인해 이러한 약물의 추가 임상 적용에 어려움이 있습니다.222,227

Signaling pathways linked to AD pathogenesis

Neuroinflammatory signaling

Several pathological factors in AD, such as Aβ, pro-inflammatory cytokines, and oxidative stress, activate microglia and initiate downstream signaling pathways such as MAPK, NF-κB, and PI3K/Akt. The activation of these pathways further promotes the activation of microglia and the production of inflammatory mediators, exacerbating neurotoxicity.238,239,240 ERK, JNK, and p38 MAPK are three primary MAPK signaling pathways that may activate transcription factors such as AP-1 and NF-κB to release pro-inflammatory cytokines like TNF-α, IL-1β, and NO.241,242 NF-κB can be co-regulated by multiple pathways including MAPK and PI3K/Akt to enhance transcriptional activity, thus promoting the expression‎ of pro-inflammatory and pro-oxidant enzyme genes.239,243,244 A recently identified microRNA, miR-25802, found to be overexpressed in AD, likely plays a crucial role in exacerbating disease pathology. This microRNA may regulate the polarization of microglial cells towards a pro-inflammatory phenotype through the modulation of the KLF4/NF-κB signaling pathway. Such alterations can further aggravate key pathological features in the 5xFAD mouse model including increased deposition of Aβ plaques and deficits in learning and memory.245 The NF-κB signaling pathway significantly impacts the expression‎ of components related to the NLRP3 inflammasome, such as NLRP3 protein, ASC, pro-IL-1β, and pro-IL-18. The NLRP3 inflammasome activates caspase-1 through its assembly and activation processes. Activated caspase-1 can cleave gasdermin D (GSDMD), triggering pyroptosis and releasing IL-1β, IL-18, and ASC specks into the extracellular environment. This may exacerbate the spread of inflammation and neuronal death.246,247,248,249 

알츠하이머병 발병과 관련된 신호 경로

신경 염증 신호

Aβ, 전 염증성 사이토카인, 산화 스트레스와 같은

AD의 여러 병리학적 요인은

미세아교세포를 활성화하고

MAPK, NF-κB, PI3K/Akt와 같은 다운스트림 신호 경로를 개시합니다.

이러한 경로의 활성화는

미세아교세포의 활성화와 염증 매개체의 생성을 더욱 촉진하여

신경독성을 악화시킵니다.238,239,240

ERK, JNK, p38 MAPK는 AP-1, NF-κB와 같은 전사인자를 활성화하여

TNF-α, IL-1β, NO 같은 염증성 사이토카인을 방출할 수 있는

3가지 주요 MAPK 신호 전달 경로입니다.241,242

NF-κB는 MAPK 및 PI3K/Akt를 포함한 여러 경로에 의해

공동 조절되어 전사 활동을 강화함으로써

염증 및 항산화 효소 유전자의 발현을 촉진할 수 있습니다.239,243,244

최근에 확인된 마이크로RNA인 miR-25802는

AD에서 과발현되는 것으로 밝혀져

질병 병리 악화에 중요한 역할을 할 가능성이 높습니다.

이 마이크로RNA는 KLF4/NF-κB 신호 경로의 조절을 통해

미세아교세포가 염증성 표현형으로 분극화되는 것을 조절할 수 있습니다.

이러한 변화는

Aβ 플라크의 침착 증가, 학습 및 기억력 결손 등

5xFAD 마우스 모델의 주요 병리학적 특징을 더욱 악화시킬 수 있습니다.245

NF-κB 신호 경로는 NLRP3 단백질, ASC, pro-IL-1β 및 pro-IL-18과 같은 NLRP3 인플라마좀 관련 성분의 발현에 상당한 영향을 미칩니다. NLRP3 인플라마좀은 조립 및 활성화 과정을 통해 카스파제-1을 활성화합니다. 활성화된 카스파제-1은 가스더민 D(GSDMD)를 절단하여 발열 증상을 유발하고 IL-1β, IL-18 및 ASC 얼룩을 세포 외 환경으로 방출할 수 있습니다. 이는 염증의 확산과 신경세포 사멸을 악화시킬 수 있습니다.246,247,248,249

Additionally, the connection between NF-κB signaling and NLRP3 inflammasome activation with AD tau pathology has garnered significant attention. Inactivated NF-κB pathways in microglia may reduce the seeding and amplification of tau proteins in microglia, thus rescuing cognitive deficits in young PS19 mouse models, yet the accumulation of tau inclusions in neurons of aged PS19 mice warrants further investigation.250 According to recent studies, pro-inflammatory cytokines like IL-1β may induce an increase in tau transcription in human primary neurons by activating the NF-κB signaling pathway in neurons. Brain-derived tau proteins may activate the inflammatory response in microglia via the TLR2/MyD88/NF-κB pathway.251 Research by Ising et al. suggests that tau proteins can activate the NLRP3 inflammasome, which then promotes excessive tau phosphorylation and aggregation by affecting specific tau kinases and phosphatases.252 These findings reveal the complex interplay between inflammatory responses and tau pathology, providing a more comprehensive understanding of AD’s molecular mechanisms. The activation of the cGAS-STING signaling pathway in AD also plays a crucial role in neuroinflammation. Studies by Xie et al. found that the abnormal accumulation of double-stranded DNA in the cytoplasm may bind to the cytoplasmic DNA sensor (cGAS), thereby specifically triggering the STING-interferon (IFN) signaling pathway in microglia, promoting the expression‎ and secretion of inflammatory cytokines. The relationships between microglia and other cells, such as astrocytes and neurons, further extend the scope of inflammation, forming a complex network of inflammatory regulation.253,254 

It is noteworthy that persistent neuroinflammation may lead to the infiltration of peripheral immune cells (such as T cells, B cells, monocytes, and neutrophils), yet the mechanisms of this infiltration and impacts on AD’s disease progression remain to be studied.254,255,256 A recent study using a special 3D human neuroimmune axis model explored the interactions between infiltrative peripheral immune cells and innate immune cells in AD. The study found that C-X-C motif chemokine ligand 10 (CXCL10) and its receptor CXCR3 play key roles in regulating the infiltration of CD8+ T cells into the brain, and the infiltrated CD8+ T cells appear to interact with microglia to jointly promote AD’s neurodegeneration.257 In the APP-PS1 transgenic mouse model, Unger et al. found that CD8+ T cells might affect brain activity by regulating genes associated with neuronal and synaptic functions, providing new clues about the potential mechanisms of CD8+ T cells in AD neuronal dysfunction and cognitive deficits.258 Additionally, TREM2 has emerged as a potential therapeutic target due to its potential role in early AD in modulating neuroinflammation, Aβ plaque deposition, and cognitive abilities.259 Recent research findings continue to reveal the potential mechanisms by which TREM2 plays a neuroprotective role in AD. For instance, Wang et al. suggest that the anti-inflammatory mechanisms induced by TREM2 may be associated with the PI3K-Akt-FoxO3a axis. The PI3K/Akt pathway, upregulated by TREM2, may regulate the activity and subcellular localization of FoxO3a, thereby reducing the expression‎ levels of pro-inflammatory cytokines.259 Moreover, TREM2 has been reported to bind with high affinity to C1q (the initiator of the classical complement pathway) to effectively inhibit the classical complement pathway, protecting synapses from abnormal phagocytosis and loss in AD.260

또한, NF-κB 신호와 NLRP3 인플라마좀 활성화와 AD 타우 병리 사이의 연관성은 상당한 주목을 받고 있습니다. 미세아교세포에서 NF-κB 경로를 비활성화하면 미세아교세포에서 타우 단백질의 시딩과 증폭이 감소하여 젊은 PS19 마우스 모델의 인지 결함이 완화될 수 있지만, 노화된 PS19 마우스의 신경세포에 타우 내포물이 축적되는 것은 추가 연구가 필요합니다.250 최근 연구에 따르면 IL-1β 같은 염증성 사이토카인은 신경세포에서 NF-κB 신호 경로를 활성화하여 인간의 원시 신경세포에서 타우 전사를 증가시킬 수 있는 것으로 밝혀졌습니다. 뇌에서 유래한 타우 단백질은 TLR2/MyD88/NF-κB 경로를 통해 미세아교세포에서 염증 반응을 활성화할 수 있습니다.251 Ising 등의 연구에 따르면 타우 단백질은 NLRP3 인플라마좀을 활성화하여 특정 타우 키나아제와 포스파타제에 영향을 주어 과도한 타우 인산화 및 응집을 촉진할 수 있습니다.252 이러한 발견은 염증 반응과 타우 병리 사이의 복잡한 상호작용을 밝혀 AD의 분자 메커니즘에 대해 보다 포괄적으로 이해하도록 해줍니다. 알츠하이머병에서 cGAS-STING 신호 경로의 활성화는 신경염증에도 중요한 역할을 합니다. Xie 등의 연구에 따르면 세포질에 이중 가닥 DNA가 비정상적으로 축적되면 세포질 DNA 센서 (cGAS)에 결합하여 미세 아교 세포에서 STING- 인터페론 (IFN) 신호 경로를 구체적으로 유발하여 염증성 사이토 카인의 발현과 분비를 촉진 할 수 있습니다.

미세아교세포와 성상교세포 및 뉴런과 같은

다른 세포 간의 관계는

염증의 범위를 더욱 확장하여

복잡한 염증 조절 네트워크를 형성합니다.253,254

지속적인 신경염증이

말초 면역세포(예: T세포, B세포, 단핵구, 호중구)의 침윤으로 이어질 수 있지만,

이러한 침윤의 메커니즘과 AD의 질병 진행에 미치는 영향은 여전히 연구되어야 합니다.254,255,256

특수 3D 인간 신경 면역 축 모델을 사용한 최근 연구에서는 AD에서 침윤성 말초 면역세포와 선천 면역세포 간의 상호작용을 탐구했습니다. 이 연구에 따르면 C-X-C 모티브 케모카인 리간드 10(CXCL10)과 그 수용체 CXCR3는 CD8+ T 세포의 뇌 침윤을 조절하는 데 중요한 역할을 하며, 침윤된 CD8+ T 세포는 미세아교세포와 상호작용하여 AD의 신경 퇴행을 공동으로 촉진하는 것으로 나타났습니다.257 APP-PS1 형질전환 마우스 모델에서 Unger 등은 CD8+ T 세포가 신경세포 및 시냅스 기능과 관련된 유전자를 조절하여 뇌 활동에 영향을 미칠 수 있음을 발견하여 AD 신경세포 기능 장애 및 인지 결손에서 CD8+ T 세포의 잠재적 메커니즘에 대한 새로운 단서를 제공했습니다.258 또한, TREM2는 신경염증, Aβ 플라크 침착 및 인지 능력을 조절하는 초기 AD에서의 잠재적 역할로 인해 잠재적 치료 표적으로 부상했습니다.259 최근 연구 결과에 따르면 TREM2가 AD에서 신경 보호 역할을 하는 잠재적 메커니즘이 계속 밝혀지고 있습니다. 예를 들어, Wang 등은 TREM2에 의해 유도되는 항염증 메커니즘이 PI3K-Akt-FoxO3a 축과 관련이 있을 수 있다고 제안합니다. TREM2에 의해 상향 조절되는 PI3K/Akt 경로는 FoxO3a의 활성과 세포 내 국소화를 조절하여 전 염증성 사이토카인의 발현 수준을 감소시킬 수 있습니다.259 또한 TREM2는 C1q(고전 보체 경로의 개시자)에 높은 친화력으로 결합하여 고전 보체 경로를 효과적으로 억제하여 AD에서 비정상적인 식세포증 및 손실로부터 시냅스를 보호한다고 보고되었습니다.260

Lysosomal dysfunction

Lysosomes rely on a rich array of acidic hydrolases to selectively degrade and recycle both intracellular and extracellular materials, playing a crucial role in maintaining cellular homeostasis.261 Lysosomal dysfunction is considered a critical factor in the development of many diseases,261 which may manifest as impaired acidification, abnormal expression‎ of lysosomal enzymes, lysosomal membrane stability issues, transport defects, and defects in autophagosome/endosome-lysosome fusion. These issues may disrupt lysosomal degradation pathways, including the autophagy-lysosomal pathway and endosomal-lysosomal system, leading to the accumulation of pathological proteins and damaged organelles, further disrupting the cellular environment.261,262,263 A key factor affecting lysosomal function is the pH controlled by the vacuolar (H+)-ATPase (V-ATPase), which uses the energy from ATP hydrolysis to drive H+ from the cytoplasm into the lysosome. Other factors such as Cl-, Ca2+, and Na+ ion channels/transporters also interact with the luminal pH and collectively regulate the lysosomal acidic environment.264,265 In AD, lysosomal acidification deficits may weaken the clearance of Aβ, ultimately leading to the accumulation of extracellular Aβ plaques.115 This phenomenon indicates that lysosomal-related clearance system dysfunction might be one of the early events in the progression of AD and has become a focus of current AD research. It has been reported that the PS1 holoprotein may facilitate N-glycosylation of the V0a1 subunit of V-ATPase and its trafficking from the endoplasmic reticulum (ER) to lysosomes, thereby promoting the assembly and maturation of V-ATPase.266 

However, there are inconsistent views on a series of events caused by defects in PS1, including impaired maturation of V0a1 in lysosomes, V-ATPase dysfunction, and lysosomal acidification defects.267,268 Calcium dysregulation associated with PS1 has been proposed as a potential cause of endolysosomal defects.268 Lee et al. once again affirmed the link between lysosomal acidification dysfunction and V-ATPase, further elucidating that aberrant lysosomal acidification mediates transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) overactivation, resulting in dysregulation of lysosomal calcium ions. Moreover, they demonstrated that solely reversing lysosomal calcium ion levels in cellular models failed to impact lysosomal acidity and autophagic function beneficially.269 Another study suggested that PS1 mutations may lead to the opening of another calcium ion channel, two pore segment channel 2 (TPCN2), whose markedly enhanced activity greatly promotes lysosomal calcium efflux and lysosomal alkalinization.270 Thus, the relationship among PS1 gene mutations or deficiencies, lysosomal acidification, and lysosomal calcium ion dysregulation warrants further investigation. Recent research has also revealed the impact of other AD-related genes on lysosomal dysfunction. For instance, increased phosphorylation of APP β-C-terminal fragment (βCTF) Tyr682 inhibited the assembly and activity of V-ATPase by binding to the V0a1 subunit, resulting in elevated lysosomal pH and impaired degradation capacity.271

리소좀 기능 장애

리소좀은 다양한 산성 가수분해효소에 의존하여 세포 내 및 세포 외 물질을 선택적으로 분해하고 재활용하여 세포 항상성을 유지하는 데 중요한 역할을 합니다.261 리소좀 기능 장애는 많은 질병의 발병에 중요한 요인으로 간주되며,261 산성화 장애, 리소좀 효소 비정상 발현, 리소좀 막 안정성 문제, 수송 결함, 오토파지/엔도솜-리소좀 융합의 결함 등으로 나타날 수 있습니다. 이러한 문제는 자가포식-리소좀 경로 및 엔도솜-리소좀 시스템을 포함한 리소좀 분해 경로를 방해하여 병적 단백질과 손상된 소기관의 축적을 초래하여 세포 환경을 더욱 혼란스럽게 만들 수 있습니다.261,262,263 리소좀 기능에 영향을 미치는 주요 요인은 ATP 가수분해 에너지를 사용하여 세포질에서 리소좀으로 H+를 이동시키는 진공 (H+)-ATPase (V-ATPase)에 의해 제어되는 pH입니다. Cl-, Ca2+, Na+ 이온 채널/수송체와 같은 다른 요인들도 루멘 pH와 상호작용하여 리소좀 산성 환경을 종합적으로 조절합니다.264,265 AD에서 리소좀 산성화 결핍은 Aβ의 제거를 약화시켜 궁극적으로 세포 외 Aβ 플라크의 축적으로 이어질 수 있습니다.115 이 현상은 리소좀 관련 제거 시스템 기능 장애가 AD 진행의 초기 사건 중 하나이며 현재 AD 연구의 중심이 될 수 있음을 시사하는 현상이라고 할 수 있습니다. PS1 홀로단백질은 V-ATPase의 V0a1 서브유닛의 N-글리코실화와 소포체(ER)에서 리소좀으로의 이동을 촉진하여 V-ATPase의 조립과 성숙을 촉진할 수 있다고 보고되었습니다.266

그러나 리소좀에서 V0a1의 성숙 장애, V-ATPase 기능 장애, 리소좀 산성화 결함 등 PS1의 결함으로 인한 일련의 사건에 대한 견해가 일치하지 않습니다.267,268 PS1과 관련된 칼슘 조절 장애가 리소좀 결함의 잠재적 원인으로 제안되었습니다.268 Lee 등은 리소좀 산성화 기능 장애와 V-ATPase 사이의 연관성을 다시 한 번 확인하여 비정상적인 리소좀 산성화가 과도 수용체 전위 양이온 채널 뮤코리핀 서브 패밀리 멤버 1 (TRPML1) 과활성화를 매개하여 리소좀 칼슘 이온의 조절 장애를 초래한다는 사실을 추가로 규명했습니다. 또한 세포 모델에서 리소좀 칼슘 이온 수준을 반전시키는 것만으로는 리소좀 산도 및 자가포식 기능에 유익한 영향을 미치지 못한다는 사실을 입증했습니다.269 또 다른 연구에서는 PS1 돌연변이가 또 다른 칼슘 이온 채널인 두 기공 세그먼트 채널 2(TPCN2)의 개방으로 이어질 수 있으며, 이 채널의 활동이 현저하게 강화되면 리소좀 칼슘 유출과 리소좀 알칼리화가 크게 촉진된다고 제안했습니다.270 따라서 PS1 유전자 변이 또는 결핍, 리소좀 산화 및 리소좀 칼슘 이온 조절 장애 사이의 관계는 추가 조사가 필요합니다. 최근 연구에 따르면 다른 AD 관련 유전자가 리소좀 기능 장애에 미치는 영향도 밝혀졌습니다. 예를 들어, APP β-C 말단 단편(βCTF) Tyr682의 인산화 증가는 V0a1 서브유닛에 결합하여 V-ATPase의 조립 및 활성을 억제하여 리소좀 pH를 상승시키고 분해 능력을 손상시켰습니다.271

Cholesterol metabolism

Cholesterol is abundant in the brain, serving as a critical component of the myelin sheath and the membranes of neural cells, including neurons and glial cells.272 The balance between cholesterol synthesis, transport, metabolism, and clearance is crucial for neuronal growth, synaptic plasticity, and learning and memory functions.273,274,275 In AD, cholesterol biosynthesis and catabolism are impaired, contributing to the progression of AD through mediation of Aβ, tau, inflammation, and other pathological changes.275,276 The connection between cholesterol and Aβ may be related to lipid rafts, which are cholesterol-rich microdomains on the plasma membrane. These rafts may facilitate the colocalization of APP with its cleaving enzymes, enhance the activities of β and γ secretases, and influence the endocytosis of APP, thereby mediating its amyloidogenic pathway.276,277 With the assistance of cholesterol transporter APOE, astrocyte-derived cholesterol could be transferred to neuronal membranes, regulating cholesterol-dependent lipid clusters (also known as lipid rafts) on neurons to promote Aβ generation. Differences in cholesterol levels caused by different APOE isoforms may be related to their cellular expression‎ and regulatory mechanisms.278 Additionally, different APOE isoforms have varying impacts on Aβ pathology. Compared to APOE3 and APOE2, APOE4-mediated pathways of Aβ clearance are impaired, and APOE4 exhibits a higher affinity interaction with Aβ, potentially driving a more severe Aβ plaque burden,119,121,123 making it one of the strongest genetic risk factors for AD. Cholinergic dysregulation associated with ApoE4 also contributes to tau pathology. For instance, in chimeric human cerebral organoids (chCOs), astrocytes and neurons carrying the APOE4 genotype could jointly promote tau phosphorylation in neurons, closely linked to the role of APOE4 in increasing cholesterol levels and lipid droplet content, suggesting that APOE4 may affect tau phosphorylation in AD by influencing lipid metabolism.279 Litvinchuk et al. revealed a potential synergistic effect between APOE4 and tau pathology, wherein APOE4 may induce the abnormal accumulation of certain cholesterol esters in glial cells. This accumulation subsequently triggers the activation of glial cells, the release of inflammatory cytokines, infiltration of T-cells, and synaptic damage.280 Furthermore, activation of the inflammation-related NLRP3 inflammasome signaling pathway in different types of neural cells was closely associated with high cholesterol load, which triggered neuroprotective properties in activated microglia but promoted oxidative stress in neurons, further enhancing the expression‎ of NLRP3 inflammasomes, inducing neuronal pyroptosis, and impairing the phagocytic capacity of microglia.281

콜레스테롤 대사

콜레스테롤은 뇌에 풍부하게 존재하며, 신경세포와 신경교세포를 포함한 신경세포의 수초와 막의 중요한 구성 요소로 작용합니다.272 콜레스테롤 합성, 수송, 대사, 제거 사이의 균형은 신경세포 성장, 시냅스 가소성, 학습 및 기억 기능에 중요합니다.273,274,275

알츠하이머병에서는 콜레스테롤 생합성과 이화 작용이 손상되어

Aβ, 타우, 염증 및 기타 병리학적인 변화를 매개하여

알츠하이머병의 진행에 기여합니다.275,276

콜레스테롤과 Aβ 사이의 연결은 혈장막의 콜레스테롤이 풍부한 미세 도메인인 지질 뗏목과 관련이 있을 수 있습니다. 이러한 뗏목은 APP의 분해 효소와의 공동화를 촉진하고, β 및 γ 분비 효소의 활성을 강화하며, APP의 세포 내화에 영향을 주어 아밀로이드 생성 경로를 매개할 수 있습니다.276,277 콜레스테롤 수송체 APOE의 도움으로 성상 세포 유래 콜레스테롤이 신경 세포막으로 전달되어 신경 세포의 콜레스테롤 의존성 지질 클러스터(지질 뗏목이라고도 함)를 조절하여 Aβ 생성을 촉진할 수 있습니다. 다른 APOE 동형에 의한 콜레스테롤 수치의 차이는 세포 발현 및 조절 메커니즘과 관련이 있을 수 있습니다.278 또한 다른 APOE 동형에 따라 Aβ 병리에 미치는 영향도 다양합니다. APOE3 및 APOE2와 비교하여 APOE4 매개 Aβ 제거 경로가 손상되고, APOE4는 Aβ와 더 높은 친화력 상호 작용을 나타내어 잠재적으로 더 심각한 Aβ 플라크 부담을 유발하며,119,121,123 AD의 가장 강력한 유전적 위험 요인 중 하나가 될 수 있습니다. ApoE4와 관련된 콜린성 조절 장애도 타우 병리에 기여합니다. 예를 들어, 키메라 인간 뇌 오가노이드(chCO)에서 APOE4 유전자형을 가진 성상교세포와 뉴런은 공동으로 뉴런에서 타우 인산화를 촉진할 수 있으며, 이는 콜레스테롤 수치 및 지질 방울 함량을 증가시키는 APOE4의 역할과 밀접한 관련이 있어 APOE4가 지질 대사에 영향을 주어 AD에서 타우 인산화에 영향을 미칠 수 있음을 시사합니다.279 리트빈추크 등은 APOE4와 타우 병리 사이의 잠재적 상승 효과를 밝혀냈는데, APOE4는 신경교 세포에서 특정 콜레스테롤 에스테르의 비정상적인 축적을 유도할 수 있습니다. 이러한 축적은 이후 신경교 세포의 활성화, 염증성 사이토카인의 방출, T 세포의 침윤 및 시냅스 손상을 유발합니다.280 또한, 다양한 유형의 신경 세포에서 염증 관련 NLRP3 인플라마좀 신호 경로의 활성화는 높은 콜레스테롤 부하와 밀접한 관련이 있으며, 이는 활성화된 미세아교세포에서 신경 보호 특성을 유발하지만 신경세포의 산화 스트레스를 촉진하여 NLRP3 인플라마좀의 발현을 더욱 강화하고 신경세포의 발열을 유도하며 미세아교의 식세포 능력을 손상시키는 것으로 나타났습니다.281

Mitochondrial dysfunction

Mitochondria are the primary source of cellular energy and mediate a multitude of biological processes including biosynthesis, redox balance, calcium signaling, and apoptosis, serving as the core drivers of vital activities.282,283 Observations in AD-afflicted brains of regionally reduced glucose metabolism and alterations in several mitochondrial enzyme activities suggest mitochondrial dysfunction.284 This is primarily manifested by defects in energy metabolism, increased oxidative stress, calcium ion imbalance, and abnormal mitochondrial dynamics, all potentially leading to neuronal dysfunction and even apoptosis, exacerbating the neurodegenerative changes in AD.282,285 Moreover, AD pathological biomarkers could directly impact mitochondrial function, creating a vicious cycle. Aβ inhibits the activity of key mitochondrial enzymes such as electron transport chain enzyme complex IV, pyruvate dehydrogenase (PDH), and α-ketoglutarate dehydrogenase (αKGDH), reducing the efficiency of electron transfer, diminishing ATP synthesis, and stimulating the production of ROS.286 Additionally, Aβ interacts specifically with mitochondrial Aβ-binding alcohol dehydrogenase (ABAD), impeding the binding of NAD to ABAD and inducing ROS production.287,288 The generation of ROS and the imbalance of the antioxidant system further damage mitochondrial DNA, lipids, and proteins, aggravating mitochondrial dysfunction and cellular apoptosis.283,289 

As the most common secondary messenger in cells, the importance of calcium ions is self-evident, and their homeostatic disruption is a significant factor in mitochondrial damage.290 Aβ may increase cytosolic calcium levels and impair mitochondrial calcium buffering functions through various pathways including plasma membrane receptors and calcium channels,291 enhanced ER calcium release,292 and the mitochondrial inner membrane calcium channel MCU.293,294 This leads to mitochondrial calcium overload, causing cyclophilin D (CypD) to relocate from the mitochondrial matrix to the inner membrane, promoting the formation of the mitochondrial permeability transition pore (mPTP), further inhibiting ATP synthesis, activating oxidative stress, and apoptosis.289,295 Moreover, tau is also associated with mitochondrial calcium imbalance, and due to the critical role of tau in microtubule structure and function, its abnormal phosphorylation and aggregation may adversely affect mitochondrial axonal transport, impacting local metabolic needs and overall neuronal function.296,297 Impairments in mitochondrial fission and fusion mechanisms, as well as mitophagy, are also areas of concern in AD. Alterations in the expression‎ levels of proteins related to fission/fusion processes (such as Opa1, Drp1, MFN1/2, Fis1)298 and post-translational modifications of Drp1299,300 may bias mitochondria towards excessive fission, increasing mitochondrial fragmentation, leading to damage in mitochondrial energy biology and accumulation of mitochondrial DNA damage.283,301 Fragmented mitochondria significantly obstruct mitophagy in AD, where PINK1/parkin-regulated mitophagy is a focal point of current research.302,303,304 PINK1 accumulates on the outer membrane of damaged mitochondria and activates parkin, which then ubiquitinates several mitochondrial outer membrane proteins to initiate the autophagic pathway, engulfing damaged mitochondria to maintain mitochondrial health and function.305 PINK1/parkin cascades related to Aβ, APP-CTFs, tau, and the APOE4 isoform could lead to the accumulation of damaged mitochondria.306 The accumulation of Aβ and increased p-tau, synaptic dysfunction, in turn, negatively regulate mitophagic activity, accelerating the pathological progression of AD.304

미토콘드리아 기능 장애

미토콘드리아는 세포 에너지의 주요 공급원이며 생합성, 산화 환원 균형, 칼슘 신호 전달, 세포 사멸 등 다양한 생물학적 과정을 매개하여 생명 활동의 핵심 동인으로 작용합니다.282,283 AD에 걸린 뇌에서 국소적으로 포도당 대사가 감소하고 여러 미토콘드리아 효소 활동이 변화하는 것을 관찰하면 미토콘드리아 기능 장애를 의심할 수 있습니다.284 이는 주로 에너지 대사의 결함, 산화 스트레스 증가, 칼슘 이온 불균형, 비정상적인 미토콘드리아 역학으로 나타나며, 모두 잠재적으로 신경 기능 장애와 세포 사멸로 이어져 AD의 신경 퇴행성 변화를 악화시킵니다.282,285 또한 AD 병리학 바이오마커는 미토콘드리아 기능에 직접적인 영향을 주어 악순환을 일으킬 수 있습니다. Aβ는 전자 수송 사슬 효소 복합체 IV, 피루베이트 탈수소효소(PDH), α-케토글루타레이트 탈수소효소(αKGDH) 등 주요 미토콘드리아 효소의 활동을 억제하여 전자 전달의 효율을 낮추고 ATP 합성을 감소시키며 ROS의 생성을 자극합니다.286 또한, Aβ는 미토콘드리아 Aβ 결합 알코올 탈수소효소(ABAD)와 특이적으로 상호작용하여 NAD와 ABAD의 결합을 방해하고 ROS 생성을 유도합니다.287,288 ROS의 생성 및 항산화 시스템의 불균형은 미토콘드리아 DNA, 지질 및 단백질을 더욱 손상시켜 미토콘드리아 기능 장애 및 세포 사멸을 악화시킵니다.283,289

세포에서 가장 흔한 2차 전달자로서 칼슘 이온의 중요성은 자명하며, 칼슘 이온의 항상성 파괴는 미토콘드리아 손상의 중요한 요인입니다.290 Aβ는 세포질 막 수용체 및 칼슘 채널,291 ER 칼슘 방출 강화,292 및 미토콘드리아 내막 칼슘 채널 MCU 등 다양한 경로를 통해 세포질 칼슘 수준을 높이고 미토콘드리아의 칼슘 완충 기능을 손상시킵니다.293,294 이는 미토콘드리아 칼슘 과부하로 이어져 사이클로필린 D(CypD)가 미토콘드리아 매트릭스에서 내막으로 이동하여 미토콘드리아 투과성 전환 기공(mPTP)의 형성을 촉진하고 ATP 합성을 더욱 억제하고 산화 스트레스 및 아포토시스를 활성화합니다.289,295. 또한 타우는 미토콘드리아 칼슘 불균형과도 관련이 있으며, 미세소관 구조 및 기능에서 타우의 중요한 역할로 인해 비정상적인 인산화 및 응집은 미토콘드리아 축삭 수송에 악영향을 미쳐 국소 대사 요구와 전반적인 신경 기능에 영향을 미칠 수 있습니다.296,297 미토콘드리아 분열 및 융합 메커니즘의 손상과 미토파지 또한 AD에서 관심의 영역이 되고 있습니다. 핵분열/융합 과정과 관련된 단백질의 발현 수준(예: Opa1, Drp1, MFN1/2, Fis1)298 및 Drp1299,300의 번역 후 변형은 미토콘드리아가 과도한 핵분열로 편향되어 미토콘드리아 단편화가 증가하여 미토콘드리아 에너지 생물학의 손상과 미토콘드리아 DNA 손상 축적을 유발할 수 있습니다.283,301 파편화된 미토콘드리아는 알츠하이머병에서 미토파지를 현저히 방해하며, PINK1/파킨 조절 미토파지가 현재 연구의 초점입니다.302,303,304 PINK1은 손상된 미토콘드리아의 외막에 축적되어 파킨을 활성화하고, 파킨은 여러 미토콘드리아 외막 단백질을 유비퀴틴화하여 자가포식 경로를 시작하여 손상된 미토콘드리아를 포획하여 미토콘드리아의 건강과 기능을 유지합니다.305 Aβ, APP-CTF, 타우 및 APOE4 이소폼과 관련된 PINK1/파킨 캐스케이드는 손상된 미토콘드리아의 축적을 초래할 수 있습니다.306 Aβ의 축적과 시냅스 기능 장애인 p-tau의 증가는 결과적으로 미토파지 활동을 부정적으로 조절하여 AD의 병리적 진행을 가속화합니다.304

Calcium signaling

Intracellular calcium could originate from the opening of plasma membrane calcium channels, such as voltage-gated and ligand-gated calcium channels, and the release of organelles like the ER and mitochondria.307,308,309 Calcium plays a multifaceted role in regulating gene expression‎, neurotransmitter release, membrane excitability, and inducing synaptic plasticity.310,311 Additionally, plasma membrane calcium ATPases (PMCA), the sarco/ER calcium ATPase (SERCA), the sodium-calcium exchangers (NCX), and Ca2+-binding proteins also regulate cytosolic calcium concentration.312,313,314,315 Maintaining this calcium homeostasis is fundamental to calcium signaling, and disruption in cytosolic calcium concentration gradients, as well as abnormalities in calcium signaling pathways, may lead to neurodegenerative diseases such as AD and Parkinson’s disease (PD), cardiovascular diseases, and metabolic disorders.315,316,317,318 In AD, enhanced activity of L-type VGCCs, potentially related to their interaction with Aβ/tau, promotes excessive calcium influx into cells.319 Studies have shown that using L-type calcium channel blockers could mitigate the upregulation of L-type VGCCs and abnormal calcium influx induced by Aβ.320 Ligand-gated calcium channels such as NMDAR and α7nAChR, highly permeable to Ca2+, are closely associated with Aβ.308 Overactivation of NMDARs by Aβ leads to abnormal calcium influx, triggering a cascade of downstream signaling events, resulting in dendritic spine loss, reduced distribution of NMDARs on neuronal membranes, impaired synaptic plasticity, and ultimately, cognitive decline.321,322 Complexes formed by A

β with α7-nAChR efficiently promote Aβ internalization and increased calcium influx, further affecting extracellular Aβ plaque accumulation and synaptic transmission.308 Abnormal intracellular calcium signaling could also impact various organelles such as the ER, mitochondria, and lysosomes. The impaired function of SERCA and/or overactivation of calcium release channels (InsP3R and ryanodine (RyR) receptors) on the ER could facilitate the activation of the ER stress response.307 The ER regulates the expression‎ of unfolded protein response (UPR)-related target genes by increasing the formation of transcription factors ATF4, XBP1, and ATP6, providing cellular stress tolerance. However, persistently high-stress levels may trigger ER-mediated apoptosis.323 Mitochondrial physiological functions are closely linked to calcium transfer between the ER and mitochondria, a process crucially mediated by MAMs.324,325,326 Under the influence of Aβ, the expression‎ of some MAM-related proteins, such as IP3Rs and VDAC1, is significantly increased,325,327,328 leading to mitochondrial Ca2+ overload, inhibition of normal ATP synthesis, and potential release of apoptotic signals.329 Research has found that lysosomal acidity is also within the realm of calcium regulation, where excessive Ca2+ released from the ER-resident RyR receptor can impair the function of lysosomal V-ATPase, causing lysosomal acidification defects, reducing lysosomal protease activity, and leading to the accumulation of p-tau.330

칼슘 신호 전달

세포 내 칼슘은 전압 게이트 및 리간드 게이트 칼슘 채널과 같은 원형질막 칼슘 채널의 개방과 ER 및 미토콘드리아와 같은 소기관의 방출에서 비롯될 수 있습니다.307,308,309 칼슘은 유전자 발현, 신경전달물질 방출, 막 흥분성 조절 및 시냅스 가소성 유도에 다각적인 역할을 합니다.310,311 또한, 혈장막 칼슘 ATPase(PMCA), sarco/ER 칼슘 ATPase(SERCA), 나트륨-칼슘 교환기(NCX) 및 Ca2+ 결합 단백질도 세포질 칼슘 농도를 조절합니다.312,313,314,315. 이러한 칼슘 항상성을 유지하는 것은 칼슘 신호전달의 기본이며, 세포질 칼슘 농도 구배의 붕괴와 칼슘 신호전달 경로의 이상은 AD 및 파킨슨병(PD)과 같은 신경 퇴행성 질환, 심혈관 질환, 대사 장애로 이어질 수 있습니다.315,316,317,318 AD에서 잠재적으로 Aβ/tau와의 상호 작용과 관련된 L형 VGCC의 활성 강화는 세포로의 과도한 칼슘 유입을 촉진합니다.319 연구에 따르면 L형 칼슘 채널 차단제를 사용하면 L형 VGCC의 상향 조절과 Aβ에 의해 유도되는 비정상적인 칼슘 유입을 완화할 수 있습니다.320 Ca2+에 대한 투과성이 높은 NMDAR 및 α7nAChR과 같은 리간드 게이트 칼슘 채널은 Aβ와 밀접한 관련이 있습니다.308 Aβ에 의한 NMDAR의 과활성화는 비정상적인 칼슘 유입을 유발하여 일련의 다운스트림 신호 이벤트를 유발하여 수상돌기 척추 손실, 신경막에서의 NMDAR 분포 감소, 시냅스 가소성 손상, 궁극적으로 인지 기능 저하를 초래합니다.321,322 Aβ에 의해 형성된 복합체는 A

β와 α7-nAChR에 의해 형성된 복합체는 Aβ 내재화와 칼슘 유입 증가를 효율적으로 촉진하여 세포 외 Aβ 플라크 축적과 시냅스 전달에 영향을 줍니다.308 비정상적인 세포 내 칼슘 신호는 ER, 미토콘드리아, 리소좀과 같은 다양한 소기관에도 영향을 미칠 수 있습니다. ER에서 SERCA의 기능 장애 및/또는 칼슘 방출 채널(InsP3R 및 라이노딘(RyR) 수용체)의 과활성화는 ER 스트레스 반응의 활성화를 촉진할 수 있습니다.307 ER은 전사인자 ATF4, XBP1 및 ATP6의 형성을 증가시켜 세포 스트레스 내성을 제공함으로써 UPR(언폴딩 단백질 반응) 관련 표적 유전자의 발현을 조절합니다. 그러나 지속적으로 높은 스트레스 수준은 ER 매개 세포 사멸을 유발할 수 있습니다.323 미토콘드리아의 생리적 기능은 ER과 미토콘드리아 사이의 칼슘 이동과 밀접한 관련이 있으며, 이 과정은 MAM에 의해 결정적으로 매개됩니다.324,325,326 Aβ의 영향으로 IP3R 및 VDAC1과 같은 일부 MAM 관련 단백질의 발현이 크게 증가하며,325,327,328 미토콘드리아 Ca2+ 과부하, 정상적인 ATP 합성 억제 및 잠재적인 세포 사멸 신호 방출로 이어집니다.329 연구에 따르면 리소좀 산성도 칼슘 조절의 영역에 속하며, ER 상주 RyR 수용체에서 방출되는 과도한 Ca2+는 리소좀 V-ATPase의 기능을 손상시켜 리소좀 산성화 결함을 유발하고 리소좀 프로테아제 활성을 감소시키며 p-tau의 축적을 유발할 수 있습니다.330

Insulin signaling

Insulin regulates glucose metabolism, neuronal growth and survival, synaptic plasticity, and cognition,331,332,333 functions closely linked to two main insulin signaling pathways: phosphatidylinositol 3-kinase (PI3K)-Akt and Ras/Raf-MAPK.334,335 The PI3K-Akt pathway is a crucial component of insulin signaling, and in AD brains, there is observed a decrease in IRS-associated PI3K activity and reduced phosphorylation of Akt kinase.336,337 Lower levels of Akt activation weaken the inhibition of glycogen synthase kinase-3 (GSK-3), which in turn positively affects the phosphorylation of tau protein and the production of Aβ.333,338,339 mTORC1, a downstream molecule of Akt, also serves as a critical nexus linking insulin signaling with the autophagy system. Its role in the inhibitory phosphorylation of IRS1, synaptic protein synthesis, synaptic plasticity, and autophagy regulation is significantly correlated with the accumulation of pathological protein aggregates and impaired learning and memory functions in AD. Some drugs targeting mTORC1 have been demonstrated in animal studies to effectively inhibit abnormal mTORC1 activation, thereby enhancing autophagy, reducing Aβ and tau pathology, and helping to delay cognitive decline. However, some studies express divergent views on the activity of mTORC1 in AD.340 Furthermore, the increased production of inflammatory mediators like TNF-α and the activation of stress kinases such as JNK, PKR, and IKK could promote the inhibitory serine phosphorylation of IRS-1, downregulate insulin signaling in the brain, and induce AD neurological dysfunction.331,341

인슐린 신호

인슐린은 포도당 대사, 신경세포 성장 및 생존, 시냅스 가소성 및 인지를 조절하며,331,332,333 두 가지 주요 인슐린 신호 전달 경로인 포스파티딜이노시톨 3-키나제(PI3K)-Akt 및 Ras/Raf-MAPK와 밀접한 관련이 있습니다.334,335 PI3K-Akt 경로는 인슐린 신호 전달의 중요한 구성 요소이며, AD 뇌에서는 IRS 관련 PI3K 활성의 감소와 Akt 키나아제의 인산화 감소가 관찰됩니다.336,337 낮은 수준의 Akt 활성화는 글리코겐 신타제 키나제-3(GSK-3)의 억제를 약화시켜 타우 단백질의 인산화와 Aβ.333,338,339의 생성에 긍정적인 영향을 미치며, Akt의 다운스트림 분자인 mTORC1은 인슐린 신호와 오토파지 시스템을 연결하는 중요한 넥서스 역할도 합니다. IRS1의 인산화 억제, 시냅스 단백질 합성, 시냅스 가소성 및 자가포식 조절에 대한 역할은 병적 단백질 응집체의 축적 및 알츠하이머병의 학습 및 기억 기능 장애와 상당한 상관관계가 있습니다. mTORC1을 표적으로 하는 일부 약물은 동물 연구에서 비정상적인 mTORC1 활성화를 효과적으로 억제하여 자가포식을 강화하고 Aβ 및 타우 병리를 감소시키며 인지 기능 저하를 지연시키는 데 도움이 되는 것으로 입증되었습니다. 그러나 일부 연구에서는 알츠하이머병에서 mTORC1의 활성에 대해 서로 다른 견해를 보이고 있습니다.340 또한, TNF-α와 같은 염증 매개체의 생산 증가와 JNK, PKR, IKK와 같은 스트레스 키나제의 활성화는 IRS-1의 억제성 세린 인산화를 촉진하고 뇌에서 인슐린 신호를 하향 조절하며 알츠하이머병 신경 기능 장애를 유발할 수 있습니다.331,341

Dysregulated neurotrophic signaling pathway

Neurotrophic factors not only promote the survival, growth, and differentiation of neurons but are also crucial for maintaining synaptic plasticity and neuronal signaling functions.342,343 In AD, key neurotrophic factors include NGF and brain-derived neurotrophic factor (BDNF), which exert their effects through specific receptors such as tropomyosin-related kinase (Trk) and p75NTR.15 In AD, there is a reduction in the conversion of proNGF to mature NGF and an enhancement in the degradation of mature NGF,344 leading to a deficiency in mature NGF and accumulation of proNGF in the brain. The lack of mature NGF may promote the phosphorylation of APP at T668, reducing its binding to TrkA and affecting its subcellular localization, thus increasing amyloidogenic processing of APP and Aβ production.345 The accumulation of proNGF and downregulation of TrkA (pro-survival signal) levels favor the predominance of pro-apoptotic signaling mediated by p75NTR, further promoting the degeneration of basal forebrain cholinergic neurons.346,347 Downregulation of BDNF expression‎ leads to weakened BDNF signaling in AD.348 This weakened signaling triggers the activation of JAK2/STAT3 and C/EBPβ signaling pathways in the AD brain and inhibits downstream Akt signaling molecules,349 thereby promoting the activation of asparagine endopeptidase (AEP; also called δ-secretase) to cleave APP and tau proteins.350,351 The cleaved tau fragments could bind to TrkB receptors, further inducing neuronal apoptosis.349 A study suggested that impaired BDNF nutritional signaling also stimulated the expression‎ of APP and PS1 to exacerbate amyloidogenesis.352 Similarly, Aβ can interfere with common neuroprotective signaling pathways, such as the Raf-MAPK/ERK pathway and the PI3K-Akt pathway, initiated by the binding of BDNF to TRKB, inducing cortical neurons into a dysfunctional state.353 According to recent research, microglial repopulation/self-renewal contributed to the restoration of BDNF expression‎ and activation of the BDNF/TrkB neurotrophic signaling pathway, significantly reversing cognitive deficits in 5xFAD mice. This suggests that BDNF may provide potential benefits for AD treatment through its positive modulation of impaired synaptic plasticity and cognitive memory.354

조절 장애가 있는 신경 영양 신호 경로

신경 영양 인자는 신경세포의 생존, 성장 및 분화를 촉진할 뿐만 아니라 시냅스 가소성 및 신경 신호 기능을 유지하는 데도 중요합니다.342,343 AD에서 주요 신경 영양 인자는 NGF와 뇌 유래 신경 영양 인자(BDNF)이며, 이들은 트로포미오신 관련 키나제(Trk) 및 p75NTR과 같은 특정 수용체를 통해 그 효과를 발휘합니다.15 알츠하이머병에서는 프로NGF가 성숙 NGF로 전환되는 것이 감소하고,344 성숙 NGF의 분해가 증가하여 뇌에 프로NGF가 결핍되고 축적됩니다. 성숙한 NGF가 부족하면 T668에서 APP의 인산화가 촉진되어 TrkA와의 결합이 감소하고 세포 내 국소화에 영향을 미쳐 APP의 아밀로이드 생성 처리 및 Aβ 생성이 증가합니다.345 proNGF의 축적과 TrkA(친생존 신호) 수준의 하향 조절은 p75NTR이 매개하는 친사멸 신호의 우세를 선호하여 기저 전뇌 콜린성 뉴런의 퇴행을 더욱 촉진합니다.346,347 BDNF 발현의 하향 조절은 AD에서 BDNF 신호의 약화로 이어집니다.348 이 약화된 신호는 AD 뇌에서 JAK2/STAT3 및 C/EBPβ 신호 경로의 활성화를 유발하고 하류 Akt 신호 분자를 억제하여,349 아스파라긴 엔도펩타제(AEP; δ-secretase라고도 함)의 활성화를 촉진하여 APP 및 타우 단백질을 절단합니다.350,351 절단된 타우 단편은 TrkB 수용체에 결합하여 신경세포 사멸을 더욱 유도할 수 있습니다.349 한 연구에서는 손상된 BDNF 영양 신호가 APP와 PS1의 발현을 자극하여 아밀로이드 생성을 악화시킨다고 제안했습니다.352 마찬가지로, Aβ는 BDNF와 TRKB의 결합에 의해 시작되는 Raf-MAPK/ERK 경로 및 PI3K-Akt 경로와 같은 일반적인 신경 보호 신호 경로를 방해하여 피질 뉴런을 기능 장애 상태로 유도할 수 있습니다.353 최근 연구에 따르면 미세아교세포 재생/자기 재생은 BDNF 발현의 회복과 BDNF/TrkB 신경 영양 신호 경로의 활성화에 기여하여 5xFAD 마우스의 인지 결손을 현저하게 반전시켰습니다. 이는 BDNF가 손상된 시냅스 가소성과 인지 기억에 대한 긍정적인 조절을 통해 AD 치료에 잠재적인 이점을 제공할 수 있음을 시사합니다.354

BBB dysfunction

The BBB is formed by components such as endothelial cells, astrocytes, and pericytes, along with the basement membrane, and together with other cells like microglia and neurons, they constitute the neurovascular unit (NVU).355,356 The BBB not only allows highly selective permeability of substances entering and exiting through specialized structures (seal off adjacent BECs) but also dynamically regulates cerebral blood flow through the process of neurovascular coupling, maintaining homeostasis and neuronal function in the CNS.355,357,358,359 Dysfunction of the BBB includes disruption of BBB integrity (or BBB leakage), changes in BBB transport functions, reduced cerebral blood flow, and neuroinflammation. Some evidence suggests that in AD, dysregulation of tight junction proteins, increased matrix metalloproteinase signaling, and degeneration and loss of pericytes may all contribute to BBB leakage, leading to the accumulation of numerous blood-derived neurotoxic proteins in the brain, causing neuroinflammation and oxidative stress.356,360,361,362 Disruption of the BBB may also lead to ischemic/hypoxic brain damage and increase Aβ production.358 Abnormal expression‎ of transport proteins/receptors in the BBB, such as downregulation of LRP1 which exports Aβ from the brain to the blood, impaired function of Pgp, and upregulation of RAGE that facilitates the entry of Aβ from the blood into the brain, could be potential reasons for impaired Aβ clearance and substantial accumulation in the brain.363 Reduced activity and expression‎ of the GLUT-1 transporter in the BBB suggest decreased glucose uptake and utilization by the brain,360,363 which may further exacerbate cerebrovascular degeneration, BBB breakdown, and Aβ pathology in models overexpressing APP, inducing neurodegeneration and cognitive deficits (Fig. 4).364

BBB 기능 장애

BBB는 기저막과 함께 내피 세포, 성상 세포 및 주변 세포와 같은 구성 요소로 형성되며, 미세아교세포 및 뉴런과 같은 다른 세포와 함께 신경혈관 단위(NVU)를 구성합니다. 355,356 BBB는 특수한 구조(인접한 BEC를 밀봉)를 통해 물질이 들어오고 나가는 것을 매우 선택적으로 허용할 뿐만 아니라 신경혈관 결합 과정을 통해 뇌 혈류를 동적으로 조절하여 CNS의 항상성과 신경세포 기능을 유지합니다.355,357,358,359 BBB의 기능 장애에는 BBB 완전성 파괴(또는 BBB 누출), BBB 수송 기능의 변화, 뇌 혈류 감소 및 신경 염증이 포함됩니다. 일부 증거에 따르면 알츠하이머병에서는 단단 접합 단백질의 조절 장애, 매트릭스 메탈로프로테아제 신호 증가, 주변 세포의 퇴화 및 손실이 모두 BBB 누출에 기여하여 뇌에 수많은 혈액 유래 신경 독성 단백질이 축적되어 신경 염증과 산화 스트레스를 유발할 수 있습니다.356,360,361,362 또한 BBB의 파괴는 허혈성/저산소성 뇌 손상으로 이어지고 Aβ 생산을 증가시킬 수 있습니다.358 뇌에서 혈액으로 Aβ를 배출하는 LRP1의 하향 조절, Pgp의 기능 장애, 혈액에서 뇌로 Aβ의 유입을 촉진하는 RAGE의 상향 조절과 같은 BBB에서 수송 단백질/수용체의 비정상적인 발현은 Aβ 제거 장애와 뇌에 상당한 축적의 잠재적 원인이 될 수 있습니다.363 BBB에서 GLUT-1 수송체의 활성 및 발현 감소는 뇌의 포도당 흡수 및 이용 감소를 시사하며,360,363 이는 APP를 과발현하는 모델에서 뇌혈관 변성, BBB 파괴 및 Aβ 병리를 더욱 악화시켜 신경 퇴화 및 인지 결함을 유발할 수 있습니다(그림 4).364

Fig. 4

Signaling pathways linked to AD pathogenesis. 

a Neuroinflammatory signaling. It involves interactions among various cell types, which influence neuroinflammation by activating multiple pathways. This leads to the production of inflammatory mediators and neuronal damage, accelerating the pathological progression of AD. 

b Lysosomal dysfunction. It may be related to impairments in V-ATPase-mediated lysosomal acidification and/or dysregulation of lysosomal calcium homeostasis. However, the specific mechanisms require further investigation to be definitively determined. 

c Aberrant cholesterol metabolism. 

d Mitochondrial dysfunction. Mitochondria in AD are damaged in various ways, including impairments in oxidative phosphorylation, calcium homeostasis, mtDNA, mitochondrial fusion and fission, axonal transport, and mitophagy. These dysfunctions lead to impaired energy production and increased oxidative stress.283 e Calcium signaling in AD. Under physiological conditions, calcium ions follow a strict concentration gradient. In AD, the elevated cytosolic calcium concentration and calcium-responsive signaling cascades adversely affect protein folding in the ER, energy production in mitochondria, and lysosomal acidity.307 g Insulin signaling in AD. 

f Dysregulated neurotrophic signaling pathway. 

h BBB dysfunction. The disruption of the integrity and alterations in the transport functions of BBB lead to the abnormal entry and exit of certain substances into and out of brain tissue, resulting in neuronal damage and further exacerbating the pathological progression of AD644

Clinical trials of AD

Biomarkers for AD diagnosis

The National Institute on Aging and Alzheimer’s Association (NIA-AA) proposed a research framework to define the biology of AD using Aβ deposition, pathologic tau, and neurodegeneration AT(N) biomarkers.365 The current established biomarkers mainly include imaging biomarkers, cerebrospinal fluid (CSF) biomarkers, and blood biomarkers. Molecular imaging techniques like magnetic resonance imaging (MRI) and positron emission tomography (PET) are commonly used to detect structural and functional brain activity in vivo.366 Specifically, structural MRI (sMRI) assesses hippocampal and entorhinal cortex atrophy in the medial temporal lobe, 18fluorodeoxyglucose (18FDG)-PET detects reduced glucose metabolism in the posterior cingulate and temporoparietal lobes, and PET imaging shows Aβ and tau deposition.366,367,368 However, sMRI and (18FDG)-PET indicate neurodegeneration or neuronal injury in the AT(N) framework with limitations in specifically diagnosing AD. They cannot accurately differentiate AD from other neurodegenerative diseases with similar pathologies, such as frontotemporal degeneration and TDP-43 proteinopathies with medial temporal lobe atrophy. Additionally, the atypical AD and cerebrovascular diseases may also complicate the diagnosis.2,369,370,371 Therefore, these methods typically need to be combined with other clinical information and assessment tools for a comprehensive eval‎uation of AD pathology. Amyloid PET and tau PET not only reflect the overall accumulation and spatial distribution of amyloid plaques and NFTs but may also detect abnormal brain changes earlier than neurodegeneration, thus providing opportunities for early intervention in the disease.366,371 Studies have reported that amyloid PET exhibits 90% sensitivity and specificity in diagnosing AD, and tau PET can specifically identify AD dementia from other neurodegenerative diseases, showing higher diagnostic accuracy than MRI markers.368

알츠하이머병 임상 시험

알츠하이머 진단을 위한 바이오마커

미국 국립 노화 및 알츠하이머 협회(NIA-AA)는 Aβ 침착, 병적 타우, 신경 퇴화 AT(N) 바이오마커를 사용하여 AD의 생물학을 정의하는 연구 프레임워크를 제안했습니다.365

현재 확립된 바이오마커는

주로 영상 바이오마커,

뇌척수액(CSF) 바이오마커,

혈액 바이오마커를 포함합니다.

자기공명영상(MRI) 및 양전자방출단층촬영(PET)과 같은 분자 영상 기술은 일반적으로 생체 내 뇌의 구조적 및 기능적 활동을 감지하는 데 사용됩니다.366 특히, 구조적 MRI(sMRI)는 내측 측두엽의 해마 및 내후두피질 위축을 평가하고, 18플루오로데옥시글루코스(18FDG)-PET는 후대상회 및 측두정엽의 포도당 대사 감소를 감지하며, PET 영상은 Aβ 및 타우 침착을 보여줍니다.366,367,368 그러나 sMRI와 (18FDG)-PET는 AT(N) 프레임워크에서 신경 퇴화 또는 신경 손상을 나타내며, AD를 구체적으로 진단하는 데는 한계가 있습니다. 전두측두엽 변성 및 내측 측두엽 위축을 동반한 TDP-43 단백질 병증과 같은 유사한 병리를 가진 다른 신경 퇴행성 질환과 AD를 정확하게 구분할 수 없습니다. 또한 비정형 AD 및 뇌혈관 질환도 진단을 복잡하게 만들 수 있습니다.2,369,370,371 따라서 이러한 방법은 일반적으로 AD 병리를 종합적으로 평가하기 위해 다른 임상 정보 및 평가 도구와 결합해야 합니다. 아밀로이드 PET와 타우 PET는 아밀로이드 플라크와 NFT의 전반적인 축적과 공간 분포를 반영할 뿐만 아니라 신경 퇴행보다 비정상적인 뇌 변화를 조기에 감지하여 질병의 조기 개입 기회를 제공할 수 있습니다.366,371 연구에 따르면 아밀로이드 PET는 AD 진단에서 90%의 민감도와 특이도를 보이며, 타우 PET는 다른 신경 퇴행성 질환에서 AD 치매를 구체적으로 식별하여 MRI 마커보다 높은 진단 정확도를 보인다고 보고되었습니다.368

NIA-AA’s AT(N) research framework includes CSF biomarkers such as Aβ42 (or the Aβ42/ Aβ40 ratio), phosphorylated tau (P-tau), and total tau (T-tau). Notably, P-tau181 concentration is the most accurate indicator for differentiating AD from non-AD dementia.372,373 While amyloid and tau PET and CSF biomarkers specifically indicate AD-related pathology, they are not entirely equivalent. Studies show a highly negative correlation between amyloid PET and CSF results, whereas CSF P-tau and tau PET findings are inconsistent. This discrepancy is related to their respective representations of PHFs formation and pathological tau deposition, with the latter’s higher correlation to cognitive abilities supporting tau PET as the most effective method for predicting cognitive decline in AD.365,374 A recent study indicated that within 20 years, abnormalities in CSF Aβ42, the ratio of CSF Aβ42 to Aβ40, CSF P-tau181, CSF T-tau, CSF neurofilament light chain (NfL), and hippocampal volume (as detected by sMRI) appear in sequence before the clinical diagnosis of SAD.375 This suggests that CSF biomarkers may reveal changes in the disease process earlier than imaging biomarkers.7 Therefore, selecting effective and reliable biomarkers, considering their sensitivity and specificity, as well as the potential inconsistencies among different biomarkers, is crucial for determining the nature and pathological stage of the disease in clinical practice. Recently, more CSF biomarkers reflecting other biological processes in AD have emerged, such as axonal injury and synaptic dysfunction (NfL, neurogranin (NG), synaptosomal-associated protein 25, visinin-like protein 1),366,367,372 neuroinflammation (TREM2, YKL40, S100B, glial fibrillary acidic protein (GFAP)),371,376,377,378 changes in neurotrophic protein levels (BDNF and NGF),379 BBB disruption (soluble platelet-derived growth factor receptor-β),380 and metabolic changes (sphingomyelin, ceramide, fatty acid-binding protein 3, ubiquitin C-terminal hydrolase L1).381,382 Extracellular vesicles (EV), crucial in AD pathology spread, have gained attention. Proteomic studies found elevated C1q levels in MCI and AD groups, and increased CatB concentration in CSF Aβ42-positive cases. These factors are potentially involved in early AD pathology through synaptic aberrant pruning and rapid abnormal metabolism of APP, respectively. They present potential CSF EV-related biomarkers pending further validation.383,384 

Blood biomarkers offer an economical, convenient, minimally invasive, and highly accessible diagnostic alternative.385,386,387 Many CSF biomarkers (like Aβ, P-tau, NfL, GFAP) also show promising applications in blood, with advancements in highly sensitive analytical platforms and detection techniques enhancing diagnostic precision and reliability.368,388,389 For instance, an innovative integrated proteomic assay accurately measured levels of 21 AD-related blood biomarkers, which jointly eval‎uated AD from five dimensions: neurodegeneration, inflammation, innate immunity, vascular function, and metabolic activity. Machine learning models built on this dataset have accurately classified AD/MCI and Aβ pathology across different ethnicities, demonstrating potential benefits in early disease screening, pathology progression monitoring, and assessing the clinical efficacy of treatments.390 In summary, the emergence of AT(N) and non-AT(N) biomarkers has significantly improved the accuracy of AD diagnosis. The use of “composite biomarker panel”390 (effective combination of biomarkers) could comprehensively reflect the biological state of AD and enhance diagnostic accuracy. This is of great importance for differentiating MCI/AD patients from cognitively normal individuals, distinguishing AD from other neurodegenerative diseases, and even identifying AD subtypes. However, AD-related comorbidities may reduce the diagnostic value of biomarkers.391,392,393 For example, coexisting αSyn pathology in AD correlates with lower CSF P-tau181 and NG levels,394 while comorbidity like hypertension lowers plasma Aβ concentration but increases plasma P-tau181 and P-tau217 levels.388,395 Future research should focus on developing more AD-specific biomarkers while also identifying biomarkers for non-AD-related diseases, aiding in a clearer understanding of AD pathology and accurately distinguishing AD from other neurodegenerative diseases.368

NIA-AA의 AT(N) 연구 프레임워크에는 Aβ42(또는 Aβ42/ Aβ40 비율), 인산화 타우(P-tau), 총 타우(T-tau)와 같은

CSF 바이오마커가 포함됩니다.

특히 P-tau181 농도는 AD와 비AD 치매를 구별하는 가장 정확한 지표입니다.372,373 아밀로이드와 타우 PET 및 CSF 바이오마커는 AD 관련 병리를 구체적으로 나타내지만, 완전히 동일하지는 않습니다. 연구에 따르면 아밀로이드 PET와 CSF 결과 사이에는 매우 음의 상관관계가 있는 반면, CSF P-tau와 타우 PET 결과는 일치하지 않는 것으로 나타났습니다. 이러한 불일치는 PHF 형성과 병적 타우 침착에 대한 각각의 표현과 관련이 있으며, 후자의 인지 능력과의 높은 상관관계는 타우 PET가 알츠하이머병의 인지 기능 저하를 예측하는 가장 효과적인 방법이라는 것을 뒷받침합니다.365,374 최근 연구에 따르면 20년 이내에 CSF Aβ42, CSF Aβ42 대 Aβ40의 비율, CSF P-tau181, CSF T-tau, CSF 신경섬유 경쇄(NfL), 해마 부피(sMRI로 감지)의 이상이 SAD 임상 진단 전에 순차적으로 나타나는 것으로 나타났습니다.375 이는 CSF 바이오마커가 영상 바이오마커보다 질병 과정의 변화를 조기에 발견할 수 있음을 시사합니다.7

따라서 임상에서 질병의 본질과 병리학적 단계를 결정하기 위해서는 민감도와 특이성, 서로 다른 바이오마커 간의 잠재적 불일치를 고려하여 효과적이고 신뢰할 수 있는 바이오마커를 선택하는 것이 중요합니다. 최근에는 축삭 손상 및 시냅스 기능 장애(NfL, 뉴로그라닌(NG), 시냅토솜 관련 단백질 25, 비시닌 유사 단백질 1),366,367,372 신경염증(TREM2, YKL40, S100B, 아교섬유산성 단백질(GFAP)),371,376,377,378 신경 영양 단백질 수치 변화(BDNF 및 NGF),379 BBB 파괴(수용성 혈소판 유래 성장 인자 수용체-β),380 및 대사 변화(스핑고마이엘린, 세라마이드, 지방산 결합 단백질 3, 유비퀴틴 C-말단 가수분해효소 L1)가 있습니다. 381,382 AD 병리 확산에 중요한 세포외소포체(EV)가 주목받고 있습니다. 프로테오믹스 연구에 따르면 MCI 및 AD 그룹에서 C1q 수치가 상승하고 CSF Aβ42 양성 사례에서 CatB 농도가 증가하는 것으로 나타났습니다. 이러한 인자들은 각각 시냅스 이상 가지치기와 APP의 빠른 비정상적 대사를 통해 초기 AD 병리에 잠재적으로 관여할 수 있습니다. 이들은 추가 검증을 기다리는 잠재적인 CSF EV 관련 바이오마커를 제시합니다.383,384

혈액 바이오마커는 경제적이고 편리하며 최소 침습적이고 접근성이 높은 진단 대안을 제공합니다.385,386,387 많은 CSF 바이오마커(Aβ, P-tau, NfL, GFAP 등)도 고감도 분석 플랫폼과 검출 기술의 발전으로 진단 정밀도와 신뢰성이 향상되면서 혈액에서 유망한 응용 가능성을 보여주고 있습니다.368,388,389 예를 들어, 혁신적인 통합 단백질체 분석법은 신경 퇴화, 염증, 선천성 면역, 혈관 기능, 대사 활동 등 5가지 측면에서 알츠하이머병을 평가하는 21가지 알츠하이머병 관련 혈액 바이오마커의 수치를 정확하게 측정했습니다. 이 데이터 세트를 기반으로 구축된 머신러닝 모델은 다양한 인종에 걸쳐 AD/MCI 및 Aβ 병리를 정확하게 분류하여 조기 질병 선별, 병리 진행 모니터링, 치료의 임상적 효능 평가에서 잠재적 이점을 입증했습니다.390 요약하면, AT(N) 및 비AT(N) 바이오마커의 출현으로 AD 진단의 정확도가 크게 향상되었습니다. “복합 바이오마커 패널"390 (바이오마커의 효과적인 조합)을 사용하면 AD의 생물학적 상태를 포괄적으로 반영하고 진단 정확도를 높일 수 있습니다. 이는 MCI/AD 환자를 인지적으로 정상적인 사람과 구별하고, AD를 다른 신경 퇴행성 질환과 구별하며, 심지어 AD 아형을 식별하는 데 매우 중요합니다. 그러나 AD 관련 동반 질환은 바이오마커의 진단 가치를 떨어뜨릴 수 있습니다.391,392,393 예를 들어, AD에서 공존하는 αSyn 병리는 낮은 CSF P-tau181 및 NG 수치와 상관관계가 있으며,394 고혈압 같은 동반 질환은 혈장 Aβ 농도를 낮추지만 혈장 P-tau181 및 P-tau217 수치를 증가시킵니다.388,395 향후 연구는 더 많은 AD 관련 바이오마커를 개발하는 동시에 비AD 관련 질환의 바이오마커를 식별하여 AD 병리에 대한 명확한 이해를 돕고 AD와 다른 신경 퇴행성 질환을 정확하게 구별하는 데 초점을 맞춰야 합니다.368

Clinical drugs

Traditional AD drugs (Fig. 5) are categorized into two classes: AChEIs (tacrine (3), donepezil (4), rivastigmine (5), galantamine (6)) and NMDA receptor antagonists (memantine (7)).396 AChEIs boost postsynaptic stimulation by increasing both the level and the action duration of ACh, thereby enhancing cognitive and behavioral functions in patients.397 Tacrine (3) was approved for AD treatment in 1993 and pulled from the market in 2013 due to its liver toxicity. Nevertheless, it has potential in the study of multitarget-directed ligands.30,398,399 Second-generation AChEIs, including donepezil (4), rivastigmine (5), galantamine (6), are more selective. They exhibited fewer side effects or improved pharmacokinetic profiles, establishing them as first-line drugs for AD.98,400 Although these drugs have been widely used, ongoing research focuses on optimizing dose, dosage form, routes of administration, and combination therapies to minimize adverse effects and improve patient compliance as much as possible.401,402,403 The donepezil (4) transdermal patch, named Adlarity, was FDA-approved in 2022 for treating mild, moderate, and severe dementia of the Alzheimer type.404 Its weekly dosing frequency showed bioequivalence to daily oral administration at the same dosage while presenting fewer gastrointestinal adverse events than oral administration. This also offers greater convenience compared to the once-daily rivastigmine (5) patch.405 The application of nanocarriers is also being explored to deliver these cholinesterase inhibitors through intranasal administration, intravenous injection, and other methods. Nanocarriers play a crucial role in increasing drug concentrations, slowing drug release, and achieving excellent bioavailability.401,406,407 Furthermore, the combination use of appropriate cholinesterase inhibitors, such as donepezil (4) and galantamine (6), or the combination of cholinesterase inhibitors with other neurologic drugs, metal chelators, or antioxidants, may yield surprising effects in the management of cholinergic drugs in AD, including efficacy, tolerability, and safety.402,408 Memantine (7) is an FDA-approved NMDA receptor antagonist for the treatment of moderate to severe stages of AD. It modulates glutamate transmission and dopamine receptors, exhibiting certain efficacy in improving patients’ cognitive function, daily living abilities, and behavior.409,410 Namzaric (8, fixed-dose combination memantine (7) extended-release/donepezil (4)) also provides another treatment option for patients with moderate to severe AD.51 These drugs primarily function by modulating neurotransmitter levels but cannot alter the course of the disease,409,411 which are instructive for designing new drugs. In 2017, a review412 proposed “disease modifying therapy for AD”, which aims to intervene in the fundamental biological mechanisms to halt the disease’s progression and provide enduring therapeutic benefits to patients. Sodium oligomannate (9, GV-971), an oligosaccharide extracted from marine algae, was conditionally approved in China in 2019 amidst ongoing debates regarding its mechanism of action and therapeutic efficacy.54,413 Sodium oligomannate (9, GV-971) was postulated to counteract AD by inhibiting neuroinflammation triggered by gut dysbiosis and disrupting the formation of Aβ fibrils.56,414 Further research indicated that sodium oligomannate (9, GV-971) altered the composition and abundance of the gut microbiome in a sex-dependent manner in both APPPS1-21 and 5xFAD models. This modulation influenced microbial metabolism and peripheral inflammation, regulated the activation state and functionality of microglia, and thereby reduced neuroinflammation and amyloidosis.415 Currently, two phase IV clinical trials (NCT05181475 and NCT05058040) are ongoing to further investigate its efficacy and safety, with an expected continuation until 2025. Aducanumab (1), lecanemab (2), and donanemab (10) are monoclonal antibodies targeting Aβ, each of which has met with differing outcomes: Aducanumab (1)416,417 received controversial FDA accelerated approval in 2021; Lecanemab (2)61 gained traditional approval in 2023; Donanemab (10)63 has completed phase III trials and is in the process of market authorization. Their status is closely linked to their mechanisms. Aducanumab (1) binds to 3-7 amino acids of Aβ, targeting soluble oligomers and insoluble fibrils.418,419 Lecanemab (2), associated with the E22G Aβ,420 showed stronger binding to soluble Aβ aggregates (oligomers and protofibrils) than aducanumab (1).421 Donanemab (10) targets pyroglutamate-modified Aβ, binding specifically to plaques.419 All three have shown efficacy in clearing Aβ plaque and slowing cognitive decline, but the risks of amyloid-related imaging abnormalities (ARIA) and their treatment costs are noteworthy.422,423,424 Brexpiprazole (11), commonly prescribed for depression and schizophrenia, targets serotonin, dopamine, and norepinephrine receptors. It is known to help mitigate agitation in individuals with AD.425,426,427 These innovative medicines delve deeper into AD mechanisms and present diverse target choices, holding the potential to halt or reverse AD progression. Further studies are needed to understand drug mechanisms, assess long-term efficacy, and ensure safety. In addition, the unfavorable risk-benefit ratio in AD makes drug repurposing a common approach. The long, high-cost, and resource-heavy process of developing AD medications, coupled with their high rate of failure, has led to growing interest in repurposing medications originally designed for other conditions, including cancer, cardiovascular diseases, psychiatric disorders, diabetes, and other neurological diseases.428,429 These drugs are noted for their extensive safety and tolerance profiles, as well as their potential for multiple uses.428,430 Additionally, the advancement of artificial intelligence (AI)-based computational tools is facilitating drug repurposing, presenting a promising strategy AD drug development.431,432,433

Fig. 5

Approved drugs for AD by FDA/China. Notably, the definition of disease-modifying therapies, capable of producing enduring and impactful changes in the clinical progression of AD, was first proposed in 2017.412 (The numbers 1, 2,…… 8, 9 in the figure represent the drug identifiers defined by the authors)

Full size image

As documented on ClinicalTrials.gov, the AD research landscape encompasses 187 clinical trials, spanning phase I, II, and III, specifically targeting AD and MCI attributed to AD. Among these trials, 36 drugs are in phase III, 87 in phase II, and 31 in phase I.434 The major mechanisms of action center around: 1) neurotransmitter receptors, including AChE, NMDA receptor, 5-hydroxytryptamine receptor, nicotinic α7 receptor, and adrenoceptor; 2) Aβ, including the reduction of Aβ production (such as γ-secretase inhibitors and modulators, BACE1 inhibitors, and α-secretase activators), prevention of Aβ aggregation, and enhancing Aβ clearance (vaccines and antibodies); 3) tau proteins (phosphorylation modulators, aggregation inhibitors, microtubule stabilizers, antibodies, and vaccines); and 4) inflammation (NSAIDs, microglia modulators).434,435,436,437 The majority of phase II and III trials center around neurotransmitter receptors and Aβ mechanisms, while tau and inflammation drugs are more prominent in phase II, often featuring repurposed compounds. Typical/Representative AD drugs in advanced clinical stages are detailed in Table 1. Semagacestat (12, LY-450139) was the first γ-secretase inhibitor to enter phase III clinical trials. A clinical trial (NCT00594568) aimed at assessing the long-term progression of AD found deterioration in cognitive and functional status across all trial groups. Additionally, participants experienced adverse reactions such as gastrointestinal symptoms, skin cancer, and infections, which are speculated to be related to the inhibition of other γ-secretase substrates, including notch, CD44, ErbB4, and cadherin.438,439,440,441 Avagacestat (13, BMS-708163) is an orally administered γ-secretase inhibitor that exhibited greater selectivity for APP-C99 compared to semagacestat (12, LY450139).440 Phase I studies indicated its effectiveness in reducing Aβ levels. However, during a phase II study assessing its safety and tolerability in patients with prodromal AD (NCT00890890), adverse events including gastrointestinal issues and skin cancer were observed in the high-dose treatment group.442 Researchers have explored inhibiting β-secretase (BACE1) as an alternative to γ-secretase inhibitors due to its higher selectivity for APP, aiming to reduce Aβ production.443 Umibecestat (14, CNP520), a fourth-generation BACE1 inhibitor, initially showed good safety and tolerability in early clinical studies.444,445 However, two phase II/III trials (NCT02565511 and NCT03131453), conducted on older individuals with high risk of AD (carriers of the APOE4 allele) but without cognitive impairment, were terminated prematurely. This decision was made due to observations of mild cognitive decline and brain atrophy in participants.446,447 Elenbecestat (15, E2609), a fourth-generation BACE1 inhibitors, was among the last BACE1 inhibitors to reach phase III clinical trials.448 A phase III trial (NCT02956486) assessing effectiveness and safety in early-stage AD patients was terminated due to an unfavorable risk-benefit ratio. More specifically, literature446,449 indicates that the termination was due to the lack of help in cognition and the emergence of side effects such as nightmares, weight loss, rash, and liver damage. ALZ-801 (16), an orally administered small molecule drug with tramiprosate as its active ingredient, exhibited effective anti-Aβ oligomer activity without binding to plaques, potentially reducing the risk of ARIA associated with plaque clearance.450,451 In interim results from its phase II trial (NCT04693520), the drug lowered biomarker levels and showed the potential to slow the decline in memory and learning abilities in early AD patients carrying the APOE4 gene (either APOE4/4 or APOE3/4).425 The ongoing phase III clinical trial (NCT04770220) aims to further validate these positive results regarding efficacy and safety in APOE4 homozygous individuals with early AD, with the study expected to continue until 2024. Varoglutamstat (17, formerly PQ912), the first small molecule glutaminyl cyclase inhibitor to enter phase II clinical trials, targets an enzyme that catalyzes the conversion of glutamate to pyroglutamate at the N-terminus of Aβ. This modification results in Aβ forms that are more prone to form toxic aggregates.452,453 In its phase IIa study (NCT03919162), varoglutamstat (17, formerly PQ912) demonstrated acceptable safety and tolerability, as well as a reduction in working memory decline.454 The ongoing phase IIb VIVIAD trial (NCT04498650) aims to further explore its long-term safety, tolerability, effects on cognition, and impact on AD biomarkers.455 Solanezumab (18, LY2062430) is an antibody targeting the intermediate domain of Aβ, effective against soluble, monomeric, non-fibrillar forms of Aβ, thus promoting the dissolution of plaques.456 In the initial two phase III trials (NCT00905372 and NCT00904683) eval‎uating the drug’s efficacy compared to a placebo in patients with mild to moderate AD, the drug did not significantly delay cognitive or functional decline. However, it appeared to potentially alter the disease course in patients with mild AD. In the expedition3 trial (NCT01900665), aimed at further validating the drug’s efficacy in patients with mild AD, the drug was declared unsuccessful in 2016, as it failed to meet its primary endpoints.457,458,459 Gantenerumab (19) is a subcutaneously administered antibody capable of binding to two regions of Aβ – the N-terminal and the central structural domain.460 It targets soluble oligomers, protofibrils, and plaques.461 Two phase III trials (NCT03444870 and NCT03443973) were recently terminated. In these trials, when assessing the efficacy and safety of gantenerumab (19) in participants with early (prodromal to mild) AD, the drug showed little clinical benefit in slowing cognitive decline, potentially due to limited clearance of amyloid plaques, with 5.0% participants experienced amyloid-related imaging abnormalities-effusion (ARIA-E) related side effects.461,462 Tideglusib (20), a non-ATP-competitive GSK-3β inhibitor, exhibits neuroprotective and anti-inflammatory properties.463 In its phase II study (NCT01350362), which eval‎uated the drug’s efficacy, safety, and tolerability in patients with mild to moderate AD, it did not meet some primary and secondary endpoints.464 TRx0237 (21, LMTX) is a tau aggregation inhibitor.465 All phase III trials have now been completed or terminated. Two earlier studies (NCT01689233 and NCT01689246) conducted on participants with mild AD and mild to moderate AD, respectively, indicated that the drug demonstrated good safety and potential benefits as a monotherapy.466,467 Another phase III trial (NCT03446001) aimed to further confirm‎ the safety and efficacy of 16 mg/day monotherapy compared to placebo in participants with mild to moderate AD, with results pending disclosure.468 Bepranemab (22, UCB0107), an antibody targeting the central region of tau, potentially inhibits tau aggregation and propagation.469 A phase II study (NCT04867616) for AD is undergoing to eval‎uate its efficacy, safety, and tolerability in patients with MCI or mild AD. E2814 (23) is a monoclonal antibody that targets the tau microtubule-binding region, thereby inhibiting tau protein aggregation and seed propagation.470 The drug is currently undergoing three clinical trials. A phase I/II trial (NCT04971733) aims to assess the safety, tolerability, and target engagement of E2814 (23) in participants with dominantly inherited AD (DIAD), with completion expected in 2025. The other two phase II/III trials (NCT01760005 and NCT05269394) aim to eval‎uate the efficacy of the combination of E2814 (23) and lecanemab (2) in early-onset AD. These trials respectively use the changes in cognitive measures and tau PET as their primary outcome measures and are expected to conclude in 2027. AADvac1 (24) is the first tau vaccine to enter clinical trials,469 aiming to inhibit tau aggregation, remove tau aggregates, prevent pathological spread, and slow disease progression. A phase II study (NCT02579252) eval‎uating the drug’s safety and efficacy in patients with mild AD showed that AADvac1 (24) was well-tolerated with no significant adverse reactions. However, its clinical efficacy requires further validation.471 NE3107 (25, formerly HE3286) is a small insulin sensitizer that inhibits inflammation.425 A phase III clinical trial (NCT04669028) has been completed, aimed at testing the safety and efficacy of the drug in elderly patients with mild to moderate AD. The results indicated that the drug was well-tolerated and effectively slowed down the rate of cognitive decline in participants, significantly improving cognitive function.472 ALZT-OP1 (26) is a combination treatment of cromolyn sodium and ibuprofen. It induces the transformation of microglial cells into a pro-phagocytic/neuroprotective activation state and blocks Aβ aggregation.473 ALZT-OP1 (26) has completed a phase III study (NCT02547818) assessing its safety and efficacy in subjects with evidence of early AD. The study aimed to determine whether the combination therapy of ALZT-OP1 (26) could slow down or reverse cognitive and functional decline in early-stage AD participants. AL002 (27) is a TREM2-specific monoclonal antibody that activates TREM2 to enhance microglial function, thereby reducing Aβ plaque formation and attenuating neurite dystrophy.474 A phase II study (NCT04592874) is currently underway to eval‎uate the efficacy and safety of AL002 (27) in participants with early-stage AD. Masitinib (28) is a potent and selective tyrosine kinase inhibitor targeting multiple aspects of AD, including inhibition of microglia and mast cell activation, modulation of Aβ and tau protein signaling pathways, and prevention of synaptic damage.475 It is currently undergoing a phase III clinical trial (NCT05564169). The objective of this study is to confirm‎ the efficacy of masitinib (28) as an adjunct therapy to cholinesterase inhibitors and/or memantine (7) in improving cognitive and functional abilities in patients with mild to moderate AD.476 Repurposed drugs include nilvadipine (29), a calcium channel blocker for the treatment of hypertension, and pioglitazone (30), a drug initially developed for diabetes. Nilvadipine (29) displays various properties, such as decreasing Aβ production, increasing cerebral blood flow, and exerting anti-tau and anti-inflammatory activities. A phase III trial (NCT02017340) testing the efficacy and safety of nilvadipine (29) in participants with mild to moderate AD indicated that, while the drug demonstrated good safety, it did not show significant benefits in slowing cognitive decline in AD patients.477 Pioglitazone (30) is a PPARγ agonist widely used in the treatment of T2D.478 Two phase III clinical trials (NCT01931566 and NCT02284906) assessed the safety and efficacy of the drug in participants with AD-induced MCI but were terminated due to insufficient efficacy.

Table 1 Representative AD drugs in late clinical stages against different target types (sourced from https://clinicaltrials.gov) (The numbers 12, 13,…… 30 in the table represent the drug identifiers defined by the authors)

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In summary, the development of AD drugs has faced numerous challenges. Factors contributing to the suboptimal performance of drugs include the selection of drug targets, the use of biomarkers and animal models in experimental designs, and other issues such as late treatment initiation, dose-dependent side effects, challenges in BBB permeability, and the heterogeneous presentation of patients.182,479,480 In the extensively researched Aβ hypothesis, Aβ stands as the most direct drug target. However, the structural polymorphism of Aβ, including monomers, soluble oligomers, protofibrils, and amyloid plaques, along with numerous pathogenic variants, complicates the selection of precise targets and adds to the complexity of designing effective drugs.481 When Aβ antibodies, such as bapineuzumab (31), did not yield significant therapeutic effects, research shifted towards inhibiting the formation of Aβ.109,170 However, the side effects associated with targeting β- and γ-secretases arise because these enzymes have a wide range of substrates that are vital in other physiological processes.170 In addition, the overemphasis on the Aβ hypothesis has also hindered the emergence of diverse new targets.482,483 Biomarkers play a crucial role in patient selection, biological effect detection, dose optimization, and monitoring response progress, with recent approvals of Aβ monoclonal antibodies benefiting from new and accurate biomarkers.83,423 The disparity in drug performance between preclinical and human trials has driven the evolution of animal models. Current AD animal models have shifted from single genetic mutation models to multi-gene transgenic models, and consider non-genetic pathogenic factors and species differences to more accurately simulate the AD progression process.484,485,486,487 While immunotherapy appears to be the most advanced therapeutic strategy, primarily targeting traditional targets such as Aβ and tau, a noticeable paradigm shift is occurring toward small-molecule therapeutic modalities.435 These modalities, characterized by their simplicity, maturity, and adaptability, provide a promising avenue for emerging targets. The development of a new generation of small-molecule drugs for AD is thus an exciting prospect. Furthermore, diverse mechanisms of inhibition, including selective, dual-targeted, allosteric, covalent, PROTACs, and PPI-targeted approaches, are enhancing drug-like properties, safety, and efficacy. This multifaceted approach aims to expedite the development of valuable drugs for both traditional and emerging targets, streamlining the drug development cycle and mitigating associated challenges.

Potential therapeutic drugs

The multifactorial nature of AD onset, coupled with the complex interactions among these factors, poses significant challenges to drug development. The limited efficacy of traditional medications, combined with the high failure rates in clinical drug development due to insufficient efficacy or adverse effects, has raised the bar for the development of the next generation of AD drugs. These drugs aim to furnish a repertoire of diverse and precise treatments tailored to individual patients and their distinct pathological processes. Progress in understanding the pathophysiological mechanisms, combined with advancements in drug development technologies, has paved the way for the discovery of novel drugs. Details of next-generation compounds in AD are outlined in Table 2.

Table 2 Development of next-generation compounds in AD (The numbers 32, 33, 34…… in the table represent the compound identifiers defined by the authors)

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Selective inhibitors

Given the association of pan-inhibitors with cytotoxicity and adverse events, coupled with a deepening understanding of the physiological functions of pathological proteins, the development of selective inhibitors has advanced significantly.488,489,490 These inhibitors are capable of specifically targeting categories, subtypes, and structural domains,491 potentially providing more pronounced benefits in terms of efficacy, safety, and tolerability.67 Kadsuranin [(+)-2] (32) and gomisin N [( − )-2] (33), which are two stereoisomers of schisandrin B extracted from the fruits of S. chinensis, have been shown to effectively inhibit GSK-3β in an ATP-competitive manner. Administering these compounds has been shown to effectively mitigate memory deficits and markedly reduce the expression‎ of phosphorylated tau in the hippocampus in the APP/PS1 double-transgenic mice.492 Targeting less conserved substrate binding sites, as opposed to ATP binding sites, might offer advantages in terms of drug specificity, functional regulation, and safety.493,494 For example, compound 34 demonstrated these benefits.495 As the role of GSK-3α in promoting Aβ production and tau phosphorylation in AD models is recognized, selective inhibition of GSK-3α has emerged as a promising therapeutic strategy.494,496,497 The GSK-3α ATP-competitive inhibitor 35 could cross the BBB and significantly reduce tau phosphorylation at pThr231 in neonatal rat brains, potentially delaying early pathological progression in AD.497 It is noteworthy that simultaneous inhibition of both GSK-3α and GSK-3β could excessively activate the wnt/β-catenin pathway, leading to abnormal cell proliferation and other detrimental effects.496,498 Therefore, the ideal state for selective drugs is to ensure efficacy while providing a suitable therapeutic window for safety. For instance, the selective GSK3β inhibitor OCM-51 (36) could achieve a beneficial balance between reducing tau phosphorylation and preventing overactivation of the β-catenin signaling pathway at appropriate doses.499 Additionally, leveraging the dynamic changes of targets may be a potential strategy for developing selective inhibitors. Given that overexpression‎ of dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) may influence the initial progression of AD through mechanisms including the hyperphosphorylation of pathologically relevant substrates such as tau, APP, PS1, regulation of axonal transport of APP, and participation in the selective splicing of tau pre-mRNA,500,501,502 the compound dp-FINDY (37) effectively targets the spatial dynamic changes in the ATP-binding site between the DYRK1A folding intermediate and the folded state, specifically acting on the folding intermediate.503 This may reduce excessive interference with numerous physiological substrates of this target and offer a novel perspective in selective drug design. Histone deacetylases (HDACs) are epigenetic regulators that modulate gene expression‎ by removing acetyl groups from lysine residues on proteins, affecting processes like cell proliferation, differentiation, and development.504,505 Among them, HDAC6 has two catalytic domains and a C-terminal zinc finger domain, interacts with tau and α-tubulin, and is involved in the degradation of protein aggregates, mitochondrial transport, and cognitive memory,506,507,508,509 making it relevant to AD pathology. HDAC6 inhibitors typically consist of three parts: a zinc-binding group (ZBG), a cap group, and a hydrocarbon motif connecting the cap and ZBG.510,511 Their selectivity often involves strong hydrophobic interactions between the cap group and a large surface area on HDAC6, known as the “L1 loop pocket”.507,512 Compound 38, incorporating cap group of melatonin and ferulic acid, enhanced HDAC6 selectivity while providing significant antioxidant capacity, alleviating spatial working and non-spatial long-term memory deficits in Aβ25-35-injected mice at lower doses.513 Compound 39 achieved strong HDAC6 selectivity through interaction with another specific pocket on HDAC6, inhibiting tau hyperphosphorylation and aggregation. It demonstrated neuroprotective activity through ubiquitination mechanisms and improved learning and memory in animal models, presenting a potential therapeutic avenue for AD.514 In most cases of selective inhibitor development, research initially relies on the scaffold of lead compounds to provide basic affinity and molecular framework. Subsequent modifications enhance drug-target binding, solubility, metabolic stability, and BBB permeability. Compounds 40 and 41 were identified through a combination of docking-based virtual screening and pharmacophore modeling from an in-house oncology compound library. Their shared scaffold may offer new insights for casein kinase 1δ (CK1δ) inhibitor development.515 In AD, c-Jun N-terminal kinase3 (JNK3) activation is closely associated with neuronal damage, amyloid deposition, and the formation of tau tangles.516 Hah et al. have conducted in-depth studies on this target, continuously refining and developing several generations of compounds based on the structure of pan-JNK inhibitor 42, which was identified through an in-house kinase-focused library screening. These compounds yielded significant improvements in potency, selectivity, and pharmacokinetic properties while maintaining key interactions with JNK3.517,518,519 Recently studied compounds 43 and 44 exhibited excellent performance in three behavioral tests of homozygous APPswe/PS1dE9 double transgenic mouse models and 3xTg mouse dementia models (Fig. 6a).519

Fig. 6

a Chemical structures of selective inhibitors 32-44. b Dual-target inhibitors 45-50. c GSK-3 degrader 62, as well as PhosTACs 63 and 64. (The numbers 32, 33,…… 51, 62, 63, 64 in the figure represent the compound identifiers defined by the authors)

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The development of selective inhibitors benefits the understanding of the roles played by different targets and their subtypes in AD, and it may also reduce the risk of side effects. Some adverse effects may originate from the off-target proteins. Differences in amino acids, explicit water molecules, spatial conformation and dynamics between the target and other proteins binding sites could serve as the basis for drug selectivity. However, in AD drug development, designing inhibitors with high selectivity poses significant challenges when faced with highly conserved or homologous binding pockets. The discovery of additional pockets on the target enzyme, target optimization (identifying substitutable targets), and the use of computational tools may offer new strategies. Nevertheless, the complexity and diversity of AD mechanisms suggest the difficulties of targeting specific targets and their limited impact on the disease progression. In addition to targeting specific enzymes, drugs aim to improve efficacy and reduce adverse reactions by focusing on specific distribution and functions in the pathological stage. For instance, PROTAC technology leverages E3 ligases, which may be selectively expressed in certain tissues, to drive the targeted degradation of specific targets,520 offering significant opportunities for AD treatment. Covalent drugs also exhibit impressive performance in selective targeting,521 potentially providing novel inhibitory approaches for kinases such as CK1, which have previously only been targeted with non-covalent ATP competitive inhibitors.522 Further drug development techniques will also be discussed below, aiming to enhance drug efficacy and safety within a broader scope of selectivity.

Dual-target inhibitors

Given the multifactorial nature of AD523 and the suboptimal effects of single-target drugs,524 the search for effective dual- or multi-target inhibitors has emerged as a new research trend. These inhibitors act on one or more targets with additive or synergistic effects, aiming to increase efficacy, prolong therapeutic effects, minimize side effects, and lower drug doses.68,69,525 Compared with combined therapies, they further reduce the risk of drug-drug interactions and simplify administration, making treatment safer, more effective, and more convenient for patients.524,525 From a biochemical standpoint, growing evidence supports a link between cholinergic abnormalities and other pathophysiological features of AD, including abnormal Aβ and tau. Consequently, cholinesterase inhibitors have become a fundamental approach in AD treatment.526 Targeting both AChE and Butyrylcholinesterase (BuChE) not only alleviates cognitive impairment in AD patients by increasing ACh levels but also serves as a disease-modifying agent, delaying the formation of Aβ plaques.527,528,529 The dual inhibitor of AChE and BuChE, compound 45, significantly enhanced the learning and memory abilities of aged AD mice. The significant alleviation in Aβ burden, anti-inflammatory and antioxidative effects, and enhanced synaptic transmission activity were also observed in the hippocampus.530 Given the elevated activity of monoamine oxidase-B (MAO-B) observed in AD, dual inhibition of AChE and MAO-B holds promise for synergistic effects on cholinergic system recovery and Aβ plaque formation, along with potential benefits in alleviating oxidative stress injury.531 Ladostigil (46), an AChE/MAO-B inhibitor developed through a pharmacophore fusion strategy,532 has completed a clinical phase II trial (NCT01429623). The trial aimed to eval‎uate the safety and efficacy of low-dose ladostigil (46) in patients with MCI. The results indicated that the drug was well-tolerated and safe, seemingly possessing the potential to delay the progression of AD.533 Compound F681-0222 (47) leveraged the functional interplay between BACE1 and AChE to decrease soluble Aβ42 levels in the brain tissue of APPswe/PS1dE9 transgenic mice.534 The simultaneous modulation of AChE and GSK-3β has the potential on improving cholinergic and tau protein signaling pathways.523,535 AChE/GSK-3β inhibitors 48536 and 49,537 developed through a pharmacophore linkage strategy, exhibited promising results by significantly inhibiting tau hyperphosphorylation and ameliorating cognitive disorders in scopolamine-treated ICR mice. Additionally, inhibiting AD-related phosphodiesterases (PDEs) could consequently enhance synaptic transmission and mitigating cognitive deficiencies.538,539 Compound 50 is a dual-inhibitor of AChE and PDE4D. It exhibited exceptional neuroprotection against cell death and more substantial anti-neuroinflammatory effects in the hippocampus of AD model mice induced by Aβ25-35 than the combined treatment of donepezil (4) and rolipram (51) (Fig. 6b).540

For diseases with complex etiologies, single-target drugs often struggle to interfere with the complete network regulation of the disease and tend to produce significant toxicity. The design and application of dual-targeted and multi-targeted inhibitors place a greater emphasis on the interrelations of pathological factors, enhancing the convenience of medication for patients. Multi-target drugs can act on multiple interconnected targets in AD. Although their activity on a single target may be lower compared to single-target drugs, the synergistic effects of multi-target modulation result in a total effect greater than the sum of the individual effects, leading to better efficacy and fewer adverse reactions. The primary strategies include pharmacophore-linked and pharmacophore-merged methods.541 Although these approaches facilitate drug design on a technical level, relying on a limited set of known SARs for pharmacophores may somewhat limit the structural diversity of the drugs and narrow the range of targets. Inspiration for drug design often draws from natural products and computer-aided screening. Additionally, the physicochemical properties, pharmacokinetic characteristics, and toxicity of the drugs are critical factors that must be carefully considered during the design processes.

Allosteric modulators

Allosteric modulators typically attach to regions distinct from the orthosteric site of receptors, inducing conformational changes to regulate the affinity and/or efficacy of orthosteric ligands, or to directly modulate receptor activity with positive, negative, or neutral effects.542,543,544,545 This precise tuning of receptor activity has revitalized the development of anti-γ-secretase drugs in the field of AD. Allosteric modulators of γ-secretase encourage the production of shorter, less toxic Aβ subtypes, and even potentially minimize effects on Notch and some other substrates. Some γ-secretase modulators (GSMs) also exhibited promising safety outcomes in preclinical studies and clinical trials.546,547,548 Compared to orthosteric sites, allosteric sites often have lower conservation and greater diversity,549 providing new avenues for drug development targeting highly homologous subtypes, such as nAChR and mAChR. The α7 nAChR subtype presents a potential approach for treating AD due to its high expression‎ in cognitive function-related brain areas and interaction with Aβ.550,551 Selective positive allosteric modulators (PAMs) targeting the α7 nAChR subtype, such as compound 52, slowed the decline of episodic/working memory in amnesia mouse models. Unlike orthosteric agonists, 52 did not cause receptor desensitization even with repeated dosing, and is currently being eval‎uated in clinical trials for its efficacy and safety in mild to moderate AD patients.552 M1-mAChR positive allosteric modulators (M1-PAMs), such as BQCA (53) and PF06764427 (54), achieve subtype selectivity through allosteric effects but have significant agonistic activity that may lead to side effects like diarrhea.544,553 The respective optimized derivatives of BQCA (53) and PF06764427 (54), compounds 55.554 and 56,555 require further in vitro and in vivo studies to eval‎uate their pharmacokinetic properties and allosteric modulation effects. Moreover, achieving signaling bias through allosteric modulation could enhance the safety of M1-mAChR drugs, making it a key consideration in the development of M1-mAChR allosteric ligands.542,544,545 Beyond the cholinergic system, allosteric drugs find broad application in AD. For example, chlorphenylalic acid PS48 (57) targets PDK-1 allosteric pocket to restore Akt insulin responsiveness. The drug reduced Aβ toxicity without over-regulating insulin signaling, presenting a promising strategy for AD prevention or treatment.556 In a phase I study (NCT05077501), the novel Trk receptor PAM ACD856 (58).557 demonstrated good safety and tolerability, as well as favorable pharmacokinetic properties, potentially benefiting neurotrophic factor signaling.558 Several reviews70,559,560,561 have extensively summarized allosteric modulation strategies targeting other proteins such as GSK-3β, NMDARs, AMPA receptors, and RIPK1 (Fig. 7a).

Fig. 7

a Chemical structures and modification schemes of allosteric modulators 52-57. b covalent inhibitors 59-61. c Compounds 65-74 target the PPI network. (The numbers 52, 53,…… 57, 59, 60, 61, 65,…… 74 in the figure represent the compound identifiers defined by the authors)

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Allosteric modulation, with its distinctive features of low-conservation binding sites, subtype or even signaling pathway selectivity, saturated allosteric effects,562 and subtle-tuning of target function, exhibits strong appeal in AD drug development. Nonetheless, the discovery and development of allosteric drugs are facing challenges. Advantages of molecular docking and dynamics simulations, X-ray crystallography, and cryo-electron microscopy have facilitated the discovery of allosteric sites to enhance our understanding of allosteric modulation.563,564 However, the complexity of allosteric modulation requires a number of in vitro and in vivo studies to thoroughly assess and analyze the functional effects of compounds and the factors influencing their characteristics.564 Clearly, the potential benefits for AD cognitive deficits and the safety of allosteric drugs still need broader experimental data to support further optimization.544,546

Covalent inhibitors

Covalent inhibitors, which form covalent bonds with their target proteins, rely on the specificity and stability of these interactions to exhibit superior potency, selectivity, and duration of action. This mechanism offers patients a convenient therapeutic option.521,565 Based on experiences in cancer treatment and other diseases, the development of AD covalent drugs also has a broad prospect. In cancer therapy, covalent inhibitors often target cysteine residues with acrylamide warheads.565,566,567 Based on this, compound 59, which features an acrylamide warhead, can covalently bind to cysteine in GSK-3β. It significantly reduced the expression‎ of APP and p-tau in the hippocampus of AD mice and improved spatial learning and memory abilities.464 A widely studied Ru(III) anticancer drug, KP1019 (60), reveals a unique anti-Aβ strategy. Unlike conventional methods that inhibit Aβ production and aggregation, KP1019 (60) counteracted Aβ toxicity to neuronal cell models by promoting the formation of soluble high-molecular-weight Aβ aggregates.568 This suggests that metal-based covalent inhibitors have promising potential in AD drug development. The electrophilic warheads and targeting residues of covalent inhibitors are continuously being developed. For example, the 6H8 (61) fragment, obtained through NMR screening from the Maybridge library, may act as a covalent warhead targeting the pathological substrate APP of γ-secretase, thereby hindering Aβ production.569,570 This could be a supplementary method to avoid potential side effects of γ-secretase inhibitors.569 In summary, the application of covalent inhibitors to some undruggable targets (such as Aβ, tau, and APPTM) has broadened the possibilities of drug design. The characteristics of covalent inhibitors are expected to reduce the required dosage and frequency of administration, thereby improving patient compliance and offering a new strategy for AD treatment. However, the potential toxicity of covalent inhibitors has always been a concern. Improving the selectivity of covalent inhibitors is critical and can be optimized through various means, including adjusting the reactivity and reversibility of the electrophile (warhead),571,572 non-covalent scaffolds, dosage, etc. Relevant literature has discussed these aspects (Fig. 7b).565,567,573

PROTACs

The ubiquitin-proteasome system (UPS) is one of the primary protein degradation pathways within the cell. However, in AD, the dysfunction of this clearance pathway becomes a significant contributor to the accumulation of pathological proteins.574 The PROTACs exploit the UPS system to precisely target specific proteins, improving the accuracy and speed of protein degradation.575 Various reviews574,575 have consolidated information on PROTACs with potential applications in AD. These PROTACs target tau protein, phosphokinase GSK-3β, HDACs, BET proteins, and transthyretin (TTR)-Aβ interaction, exhibiting characteristics such as low dosage requirements, high efficacy, and high target selectivity. As technology continues to advance, PROTACs undergo continuous refinement. For example, the GSK-3 degrader PT-65 (62), developed through click chemistry, exhibited a more prolonged effect on p-tau than its GSK-3 warhead (a GSK-3 inhibitor). This may help reduce dosing frequency.576 Additionally, phosTAC7 (63)577 and tau2-8 (64)578 ingeniously leverage the flexibility of PROTACs to create targeted dephosphorylation strategies. In summary, PROTACs represent a burgeoning technology in AD drug development, specifically targeting dysfunctional enzymes, misfolded proteins, and even PPI in AD through the rational utilization of the UPS clearance system. However, PROTACs are still facing challenges. Limitations include the restricted choices of E3 ligases, primarily CRBN and VHL, and the considerable molecular weight of compounds that cause poor BBB penetration. Notably, while PROTACs can alter the existing pathological phenotype of AD, they cannot reverse the damage that has already occurred, particularly in addressing the genetic mutations associated with FAD (Fig. 6c).574

Targeting the PPI network

Protein-protein interactions (PPIs) are fundamental in maintaining cellular functions, while aberrant interactions between proteins are implicated in the pathogenesis of numerous diseases.75,579 For instance, AD is characterized by the misfolding and aggregation of Aβ and tau proteins, involving a variety of molecular mechanisms and complex networks of PPIs.580,581,582 Thus, disrupting these interactions may block some critical signaling pathways and potentially mitigate the pathological process of AD. Although large and flat PPI interfaces may be more conducive to peptide and protein drug targeting,75,583,584 small molecule inhibitors also play a role in some AD-related PPIs due to their unique advantages. For example, Aβ can interact with the leukocyte immunoglobulin-like receptor B2 (LilrB2) and negatively mediate synapses and memory.585 Compounds ALI6 (65)586 and 66587 can effectively block this interaction, which reverses the changes in cofilin signaling downstream of LilrB2 and the inhibition of neurite outgrowth, thus protecting neuronal cells from Aβ toxicity. In contrast, the interaction between Aβ and transthyretin (TTR) is a favored PPI, because it reduces Aβ aggregation and toxicity.588 Iododiflunisal (67, IDIF), luteolin (68), and three marketed drugs sulindac (69), olsalazine (70), and flufenamic (71) are small-molecule chaperones for the TTR/Aβ interaction. They all significantly reduced the caspase-3 activation in SH-SY5Y cells, protecting cells from apoptosis/death. Moreover, their good BBB penetration ability warrants their application in TTR target validation and positions them as potential candidates for AD clinical trials.589 Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2), critical for regulating anti-oxidative stress, represents a PPI targetable by covalent inhibitors.590 Its orally available inhibitor NXPZ-2 (72) effectively ameliorated Aβ-induced cognitive dysfunction in mice by increasing the expression‎ levels of Nrf2 and downstream antioxidant enzymes.590 However, issues of low solubility and lack of validation in transgenic AD models with NXPZ-2 (72) are presented, which was properly addressed by its analog 73.591 Additionally, another Keap1-Nrf2 PPI inhibitor 74, which combined conformational features significantly similar to the Keap1-Nrf2 ETGE complex, revealed the unique inhibition mechanism and provided an innovative strategy for the development of new Keap1-Nrf2 PPI inhibitors.592 In summary, inhibition or activation of fundamental pathological interactions presents an alternative therapeutic avenue for AD. PPI modulators precisely target pathological pathways in a reversible and mildly regulatory manner, preserving the physiological functions of proteins and thereby reducing severe side effects associated with excessive inhibition, thus offering higher safety levels. In addition, recent advances in computational analysis and model building also support the identification of specific, high-affinity PPI drug hits. These approaches systematically locate underutilized or optimal local interaction regions, simulating the dynamic and transient nature of PPIs, thereby presenting unlimited possibilities for efficient PPI drug discovery (Fig. 7c).593

Conclusions and prospects

AD is a progressive neurodegenerative disease characterized by declining memory and cognitive dysfunction. Pathological features such as Aβ plaques and NFTs in patients have been well documented. However, the existing hypothesis fails to fully elucidate the precise impact of these alterations on the onset and development of AD or the complex interactions among various pathological events. The focus on inflammatory responses and the immune system has led to speculation that certain pathogens such as Porphyromonas gingivalis, herpes simplex virus 1 (HSV1), and SARS-CoV-2 may play a role in AD, and the antimicrobial activity of Aβ may also partially supports the mechanism.214 Some animal studies suggested that Porphyromonas gingivalis could translocate to the brain, closely linked to the deposition of Aβ and tau and the occurrence of neuroinflammation.594,595 While some epidemiological data and preclinical studies suggest the association between HSV1 and AD, more research is needed to further validate and understand the relationship.596,597,598 Research of both HSV1-infected mice and AD mouse models has revealed the gene MAM domain containing 2 (MAMDC2) exhibits significant expression‎ in microglia, which results in high levels of I-IFNs to enhance antiviral responses in HSV1-infected mice and neuroinflammation in the AD animal model.599 HSV1 may also impact Aβ pathology through mechanisms, such as continuous production and aggregation of Aβ within infected neurons via the activation of caspase 3,600 and altering γ-secretase activity.601 Many COVID-19 patients diagnosed with some long or post-acute sequelae of COVID-19 such as brain atrophy and memory decline, greatly increasing the risk of AD.602,603 AD patients are also more susceptible to COVID-19, with higher risks of hospitalization and mortality in the patients with dementia and COVID-19.604 This suggests a correlation between the two diseases. From a genetic perspective, some genes such as APOE4 and oligoadenylate synthetase 1 (OAS1) play important roles in susceptibility to both COVID-19 and AD. APOE4 as a significant genetic risk factor for AD also interacts with angiotensin-converting enzyme 2 (ACE2) to hinder SARS-CoV-2 infection and influence inflammation levels.605 Some variants in the interferon-responsive gene OAS1 may lower its expression‎ and potentially increase the likelihood of AD and severe COVID-19, through excessive release of pro-inflammatory signals in myeloid cells such as microglia and macrophages, further leading to cell death.606 SARS-CoV-2 affects key pathological changes, such as Aβ, tau, and neuroinflammation, promoting cognitive impairment. Interaction between the SARS-CoV-2 Spike S2 subunit and γ-secretase could regulate γ-secretase cleavage of APP and increase Aβ production.607 SARS-CoV-2 may facilitate the intercellular spread of tau aggregates by forming extracellular vesicles modified with spike S protein.608 Upon entry into the host cell, it may cause cytokine storms and immune dysregulation, disrupt the BBB, and reduce Aβ clearance, ultimately resulting in neuroinflammation and Aβ aggregation.602 Additionally, the upregulation of shared pathogenic kinases in COVID-19 and AD, such as epidermal growth factor receptors, vascular growth factor receptors, Bruton tyrosine kinase, spleen tyrosine kinase, c-ABL, and JAK/STAT, suggests potential interactions between immunological and neurological mechanisms.609

The current approaches to addressing AD focus on three main aspects: prevention, early diagnosis, and treatment. Managing modifiable risk factors provides a pathway for AD prevention, which may help reducing cognitive decline and the risk of AD. In early diagnosis, various biomarkers of CSF, blood, urine,610 saliva,611 and retina,612 may contribute to comprehensively reflecting the AD pathological process, serving as potential auxiliary tools that are more convenient, cost-effective, or less invasive. Pharmacotherapy is broadly employed in AD treatment; however, the efficacy or safety of most investigational and clinical drugs is not ideal. Factors such as dose-dependent adverse reactions, the inability to penetrate the BBB and achieve effective therapeutic concentrations, and variations in patient sensitivity and metabolic capacity may all influence outcomes. Here, we elucidate the issue from the perspective of the AD nature and drug development technologies. Firstly, the nature of AD may affect the choice of medication. For instance, the deficiency or mutation in aldehyde dehydrogenase (ALDH2) may influence melatonin administration, which could potentially benefit AD patients experiencing cardiac dysfunction. A study14 found that in APP/PS1 mutant mice, the decrease in ALDH2 activity could lead to a cascade of downstream events, including disruption of mitochondrial integrity, accumulation of mitochondrial DNA in the cytoplasm, downregulation of the cGAS-STING-TBK1 signaling pathway, and inhibition of autophagy and mitophagy, ultimately resulting in cardiac disorders. Moreover, the beneficial effects of melatonin on mouse hearts, which depend on the regulation of ALDH2 activity, could not be assessed due to mutations or deficiencies in ALDH2. Secondly, appropriate drug development strategies provide the possibility of safe and effective drugs. These technologies may balance the efficacy and risk through targeting selection (single target/multiple targets, structurally similar targets, undruggable targets, active/non-active sites on targets, protein/PPI), the mode of action on targets (clearance, inhibition, or activation), and the duration and intensity of drug targets. Additionally, the burgeoning development of AI may impact AD due to its advantages in handling complex biomedical big data sets.613 AI is currently making preliminary explorations in various aspects of AD, from detection and diagnosis to understanding disease mechanisms, biomarker discovery, clinical trial design, drug discovery, and prognosis prediction. Overall, AI’s integration into various facets of AD research holds promise for advancing our understanding of the disease. 614,615,616,617,618

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