Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons
{"title":"小胶质细胞中载脂蛋白 E 的聚集通过播散 β 淀粉样蛋白沉积引发阿尔茨海默病的病理变化","authors":"Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons","doi":"10.1016/j.immuni.2024.09.014","DOIUrl":null,"url":null,"abstract":"The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (<em>APOE</em>) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis\",\"authors\":\"Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons\",\"doi\":\"10.1016/j.immuni.2024.09.014\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (<em>APOE</em>) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.\",\"PeriodicalId\":13269,\"journal\":{\"name\":\"Immunity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":25.5000,\"publicationDate\":\"2024-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.immuni.2024.09.014\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.immuni.2024.09.014","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis
The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.
期刊介绍:
Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.