Induction of Alzheimer’s disease pathology by early-life stress
Induction of Alzheimer’s disease pathology by early-life stress
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早期生活压力诱发阿尔茨海默病病理
DOI：
10.1101/2020.04.27.062729
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Haruo Okado
中科院分区：
文献类型：
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作者：
Tomoko Tanaka;Shinobu Hirai;Masato Hosokawa;Takashi Saito;Hiroshi Sakuma;Takaomi Saido;Masato Hasegawa;Haruo Okado
研究背景阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病，是一个严重的社会问题。最近，几个早期生活的因素已与AD的临床诊断的风险增加。MethodsWe研究了早期生活的压力在AD发病机制的参与使用杂合子的淀粉样前体蛋白（APP）突变小鼠（AppNL-G-F/wt）和野生型（Appwt/wt）小鼠。母亲分离被用作早期生活压力的动物范例。除了生化测试外，还进行了物体定位和恐惧条件反射测试以测量认知功能。行为测试后进行免疫组织化学分析。结果我们发现，母亲分离的Appwt/wt小鼠表现出血管狭窄和减少前额叶皮层毛细血管周细胞覆盖，而母亲分离的AppNL-G-F/wt小鼠还表现出认知功能障碍，早期形成Aβ斑块和血脑屏障破坏。在母体分离的AppNL-G-F/wt小鼠和母体分离的Appwt/wt小鼠中检测到小胶质细胞的严重活化。在早期阶段，在母体分离的AppNL-G-F/wt小鼠和母体分离的Appwt/wt小鼠的小胶质细胞中观察到形态学变化和炎症反应，以及在非母体分离的AppNL-G-F/wt小鼠的小胶质细胞中观察到形态学变化。因此，这些研究结果表明，母亲分离导致早期诱导AD病理通过血管病。
BackgroundAlzheimer’s disease (AD), a progressive neurodegenerative disorder, is a serious social problem. Recently, several early-life factors have been associated with an increased risk of a clinical diagnosis of AD.MethodsWe investigated the involvement of early-life stress in AD pathogenesis using heterozygous the amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. Maternal separation was used as an animal paradigm for early-life stress. Object location and fear conditioning tests were performed to measure cognitive functions, in addition to biochemical tests. Immunohistochemical analyses were performed after the behavioral tests.ResultsWe found that maternal-separatedAppwt/wtmice showed narrowing of vessels and decreased pericyte coverage of capillaries in prefrontal cortex, while maternal-separatedAppNL-G-F/wtmice additionally showed impairment of cognitive function, and earlier formation of Aβ plaques and disruption of the blood–brain barrier. Severe activation of microglia was detected in the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice. At the early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separatedAppNL-G-F/wtmice and maternal-separatedAppwt/wtmice, as well as morphological changes in the microglia of the non-maternal-separatedAppNL-G-F/wtmice.ConclusionsMicroglia activation induced by maternal separation in combination with the APP mutation may impairs the vascular system, leading to AD progression. These findings therefore suggest that maternal separation causes early induction of AD pathology via angiopathy.