Early-life stress induces the development of Alzheimer's disease pathology via angiopathy
Early-life stress induces the development of Alzheimer's disease pathology via angiopathy
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早期生活压力通过血管病变诱发阿尔茨海默病病理学的发展
DOI：
10.1016/j.expneurol.2020.113552
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发表时间：
2021
影响因子：
5.3
通讯作者：
Okado Haruo
中科院分区：
文献类型：
--
作者：
Tanaka Tomoko;Hirai Shinobu;Hosokawa Masato;Saito Takashi;Sakuma Hiroshi;Saido Takaomi;Hasegawa Masato;Okado Haruo
阿尔茨海默病(AD)是一种进行性神经退行性疾病，是一个重大的社会、科学和经济问题。最近发现了几个与AD临床诊断风险增加相关的早期生命因素。在本研究中，我们利用杂合淀粉样前体蛋白(APP)突变小鼠(AppNL-G-F/wt)和野生型(Appwt/wt)小鼠，研究了早期应激在AD发病中的作用。我们发现，母系分离的Appwt/wt小鼠前额叶皮质血管变窄，周细胞覆盖率降低，而母系分离的AppNL-G-F/wt小鼠还表现出认知功能障碍，Aβ斑块提前形成，血管相关小胶质细胞增加，血脑屏障破坏。在母系分离的AppNL-G-F/wt小鼠和母系分离的Appwt/wt小鼠中检测到大量的小胶质细胞激活。在早期，母系分离的AppNL-G-F/wt小鼠和母系分离的Appwt/wt小鼠的小胶质细胞出现了形态变化和炎症反应，而非母系分离的AppNL-G-F/wt小鼠则观察到了小胶质细胞的形态变化。母体分离和APP突变联合诱导的小胶质细胞激活可能会损害血管系统，导致AD进展。因此，这些发现表明，母体分离会通过血管病变导致AD相关病理的早期诱导。
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a major societal, scientific, and economic problem. Several early-life factors associated with an increased risk for the clinical diagnosis of AD have recently been identified. In the present study, we investigated the involvement of early-life stress in the pathogenesis of AD using heterozygous amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. We found that maternal-separatedAppwt/wtmice showed narrowing of vessels and decreased pericyte coverage of capillaries in the prefrontal cortex, while maternal-separatedAppNL-G-F/wtmice additionally showed the impairment of cognitive function, earlier formation of Aβ plaques, increased vessel-associated microglia, and disruption of the blood–brain barrier. Substantial activation of microglia was detected in the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice. At an early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice, and morphological changes in the microglia were observed in the non-maternal-separatedAppNL-G-F/wtmice. Microglia activation induced by maternal separation in combination with the APP mutation may impair the vascular system, leading to AD progression. These findings therefore suggest that maternal separation results in the early induction of AD-related pathology via angiopathy.