德国慕尼黑工业大学Mikael Simons等研究人员合作发现，载脂蛋白E在小胶质细胞中的聚集通过引发β淀粉样变性来启动阿尔茨海默病的病理进程。该项研究成果于2024年10月16日在线发表在《免疫》杂志上。

研究人员表示，致病性蛋白质聚集的播种性增长是阿尔茨海默病（AD）病理的基础，但这种病理级联反应如何启动尚未完全理解。散发性AD在遗传上与载脂蛋白E（APOE）以及其他与免疫、脂质和内吞功能相关的小胶质细胞表达的基因有关。

研究人员生成了一种表达HaloTag标记的APOE的转基因敲入小鼠，并优化了APOE的生化纯化实验方案，这使研究人员能够在具有淀粉样β（Aβ）淀粉样变性的小鼠和人类AD大脑尸检中鉴定出APOE的纤维状聚集物。这些对β折叠结合染料呈阳性的APOE聚集物在小胶质细胞的内吞溶酶体系统内触发了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。

综上所述，研究人员提出了一个AD中Aβ淀粉样变性起始的模型，表明小胶质细胞通过内吞作用摄取并聚集APOE可以启动Aβ斑块的形成。

附：英文原文

Title: Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis

Author: 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, Martina Schifferer, Michael Willem, Klaus-Armin Nave, Christian Haass, Thomas Arzberger, Sarah Jkel, Oliver Wirths, Gesine Saher, Mikael Simons

Issue&Volume: 2024-10-16

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 (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.

DOI: 10.1016/j.immuni.2024.09.014

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00458-8