The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

中文翻译：

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来自星形胶质细胞的 APOE 可恢复 APOE 缺陷小胶质细胞中的阿尔茨海默病 Aβ 病理和 DAM 样反应。


阿尔茨海默病 （AD） 的主要遗传风险因素 APOE4 会加速 β-淀粉样蛋白 （Aβ） 斑块的形成，但这是由小胶质细胞还是星形胶质细胞中表达的 APOE 引起的存在争议。我们在这里在 Apoe 缺陷型 AD 小鼠模型中的星形胶质细胞中表达人 APOE 亚型。这不仅足以恢复淀粉样蛋白斑块病理学，而且还在斑块周围的 Apoe 缺陷型小胶质细胞中诱导特征性转录病理反应。我们发现 APOE4 和来自星形胶质细胞的保护性 APOE2 都会增加纤维斑块沉积，但对可溶性 Aβ 聚集体的影响不同。小胶质细胞和星形胶质细胞显示出星形胶质细胞中表达的 APOE 基因型功能的特异性改变。我们的实验表明，星形胶质细胞在 APOE 介导的淀粉样斑块病理学和诱导相关小胶质细胞反应中起着核心作用。