{"title":"载脂蛋白E4在阿尔茨海默病病理中的多重作用和潜在的治疗策略。","authors":"Yongfeng Chen, Haiping Jin, Jia Chen, Jing Li, Mihnea-Alexandru Găman, Zhenyou Zou","doi":"10.1038/s41420-025-02600-y","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD), the most common dementia in the elderly, is marked by progressive cognitive decline and neurodegeneration. Core pathological hallmarks include amyloid-beta (Aβ) plaques, hyperphosphorylated tau aggregates, neuroinflammation, and metabolic dysfunction (e.g., impaired glucose utilization, mitochondrial deficits). Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for AD, interacts with these processes, yet its precise pathogenic mechanisms remain unclear. This review examines ApoE4's multifaceted contributions to AD pathogenesis, focusing on its roles in Aβ accumulation, tau hyperphosphorylation, neuroinflammatory activation, and metabolic dysregulation. We further evaluate emerging therapeutic strategies targeting these pathways, including ApoE4 modulation, anti-amyloid/tau interventions, and metabolic rescue approaches. Elucidating the molecular interplay between ApoE4 and AD pathology is critical for developing targeted therapies to modify disease progression and mitigate cognitive decline in patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"312"},"PeriodicalIF":6.1000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238274/pdf/","citationCount":"0","resultStr":"{\"title\":\"The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.\",\"authors\":\"Yongfeng Chen, Haiping Jin, Jia Chen, Jing Li, Mihnea-Alexandru Găman, Zhenyou Zou\",\"doi\":\"10.1038/s41420-025-02600-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease (AD), the most common dementia in the elderly, is marked by progressive cognitive decline and neurodegeneration. Core pathological hallmarks include amyloid-beta (Aβ) plaques, hyperphosphorylated tau aggregates, neuroinflammation, and metabolic dysfunction (e.g., impaired glucose utilization, mitochondrial deficits). Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for AD, interacts with these processes, yet its precise pathogenic mechanisms remain unclear. This review examines ApoE4's multifaceted contributions to AD pathogenesis, focusing on its roles in Aβ accumulation, tau hyperphosphorylation, neuroinflammatory activation, and metabolic dysregulation. We further evaluate emerging therapeutic strategies targeting these pathways, including ApoE4 modulation, anti-amyloid/tau interventions, and metabolic rescue approaches. Elucidating the molecular interplay between ApoE4 and AD pathology is critical for developing targeted therapies to modify disease progression and mitigate cognitive decline in patients.</p>\",\"PeriodicalId\":9735,\"journal\":{\"name\":\"Cell Death Discovery\",\"volume\":\"11 1\",\"pages\":\"312\"},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2025-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238274/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death Discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41420-025-02600-y\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-025-02600-y","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.
Alzheimer's disease (AD), the most common dementia in the elderly, is marked by progressive cognitive decline and neurodegeneration. Core pathological hallmarks include amyloid-beta (Aβ) plaques, hyperphosphorylated tau aggregates, neuroinflammation, and metabolic dysfunction (e.g., impaired glucose utilization, mitochondrial deficits). Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for AD, interacts with these processes, yet its precise pathogenic mechanisms remain unclear. This review examines ApoE4's multifaceted contributions to AD pathogenesis, focusing on its roles in Aβ accumulation, tau hyperphosphorylation, neuroinflammatory activation, and metabolic dysregulation. We further evaluate emerging therapeutic strategies targeting these pathways, including ApoE4 modulation, anti-amyloid/tau interventions, and metabolic rescue approaches. Elucidating the molecular interplay between ApoE4 and AD pathology is critical for developing targeted therapies to modify disease progression and mitigate cognitive decline in patients.
期刊介绍：
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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