PDF(Pubmed)
Abstract：
Stress is an important initiating factor in promoting Alzheimer\'s disease (AD) pathogenesis. However, the mechanism by which stress induces AD-like cognitive impairment remains to be clarified. Here, we demonstrate that DNA damage is increased in stress hormone Corticotropin-releasing factor (CRF)-treated cells and in brains of mice exposed to chronic restraint stress. Accumulation of DNA damage drives activation of cell cycle checkpoint protein kinase 1 (Chk1), upregulation of cancerous inhibitor of PP2A (CIP2A), tau hyperphosphorylation, and Aβ overproduction, eventually resulting in synaptic impairment and cognitive deficits. Pharmacological intervention targeting Chk1 by specific inhibitor and DNA damage by vitamin C, suppress DNA damage-Chk1-CIP2A signaling pathway in chronic stress animal model, which in turn attenuate AD-like pathologies, synaptic impairments and cognitive deficits. Our study uncovers a novel molecular mechanism of stress-induced AD-like pathologies and provides effective preventive and therapeutic strategies targeting this signaling pathway.
摘要：
应激是促进阿尔茨海默病(AD)发病的重要启动因素。然而,应激导致AD样认知障碍的机制仍有待阐明。这里,我们证明，在应激激素促肾上腺皮质激素释放因子（CRF）处理的细胞和暴露于慢性束缚应激的小鼠的大脑中，DNA损伤增加。DNA损伤的积累驱动细胞周期检查点蛋白激酶1（Chk1）的激活，PP2A（CIP2A）癌性抑制剂的上调，tau过度磷酸化，Aβ生产过剩,最终导致突触损伤和认知缺陷。特异性抑制剂靶向Chk1的药物干预和维生素C的DNA损伤，在慢性应激动物模型中抑制DNA损伤-Chk1-CIP2A信号通路,反过来减弱AD样病变，突触损伤和认知缺陷。我们的研究揭示了应激诱导的AD样病变的新分子机制，并提供了针对该信号通路的有效预防和治疗策略。
