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.

中文翻译：

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小胶质细胞中的载脂蛋白 E 聚集通过播种 β-淀粉样变性引发阿尔茨海默病的病理学


致病性蛋白质聚集体的种子生长是阿尔茨海默病 （AD） 发病机制的基础，但这种病理级联反应是如何开始的尚不完全清楚。散发性 AD 在遗传上与载脂蛋白 E （APOE） 和小胶质细胞中表达的与免疫、脂质和内吞功能相关的其他基因有关。我们生成了表达 HaloTag 标记的 APOE 的转基因敲入小鼠，并优化了 APOE 生化纯化的实验方案，这使我们能够鉴定 APOE 的原纤维聚集体在淀粉样蛋白β （Aβ） 淀粉样变性小鼠和人 AD 脑尸检中。这些 β 片状结合染料染色呈阳性的 APOE 聚集体在小胶质细胞溶酶体内系统内触发了 Aβ 淀粉样变性，这一过程受小胶质细胞脂质代谢和 JAK/STAT 信号通路的影响。综合这些观察结果，我们提出了一个 AD 中 Aβ 淀粉样变性发病的模型，表明小胶质细胞对 APOE 的内吞摄取和聚集可以启动 Aβ 斑块形成。