Piirainen Sami, Youssef Andrew, Song Cai, Kalueff Allan V, Landreth Gary E, Malm Tarja, Tian Li
Neuroscience Center, HiLIFE, University of Helsinki, Viikinkaari 4, FIN-00014, Helsinki, Finland.
Research Institute of Marine Drugs and Nutrition, Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; Department of Psychology and Neuroscience, Dalhousie University, 1355 Oxford St, Life Sciences Centre, Halifax, Nova Scotia B3H4R2, Canada.
Neurosci Biobehav Rev. 2017 Jun;77:148-164. doi: 10.1016/j.neubiorev.2017.01.046. Epub 2017 Feb 6.
Chronic psychosocial stress is increasingly recognized as a risk factor for late-onset Alzheimer's disease (LOAD) and associated cognitive deficits. Chronic stress also primes microglia and induces inflammatory responses in the adult brain, thereby compromising synapse-supportive roles of microglia and deteriorating cognitive functions during aging. Substantial evidence demonstrates that failure of microglia to clear abnormally accumulating amyloid-beta (Aβ) peptide contributes to neuroinflammation and neurodegeneration in AD. Moreover, genome-wide association studies have linked variants in several immune genes, such as TREM2 and CD33, the expression of which in the brain is restricted to microglia, with cognitive dysfunctions in LOAD. Thus, inflammation-promoting chronic stress may create a vicious cycle of aggravated microglial dysfunction accompanied by increased Aβ accumulation, collectively exacerbating neurodegeneration. Surprisingly, however, little is known about whether and how chronic stress contributes to microglia-mediated neuroinflammation that may underlie cognitive impairments in AD. This review aims to summarize the currently available clinical and preclinical data and outline potential molecular mechanisms linking stress, microglia and neurodegeneration, to foster future research in this field.
慢性心理社会压力日益被认为是晚发性阿尔茨海默病（LOAD）及相关认知缺陷的一个风险因素。慢性应激还会使小胶质细胞致敏，并在成年大脑中引发炎症反应，从而损害小胶质细胞对突触的支持作用，并在衰老过程中使认知功能恶化。大量证据表明，小胶质细胞无法清除异常积累的淀粉样β（Aβ）肽会导致AD中的神经炎症和神经退行性变。此外，全基因组关联研究已将几个免疫基因（如TREM2和CD33）的变异与LOAD中的认知功能障碍联系起来，这些基因在大脑中的表达仅限于小胶质细胞。因此，促进炎症的慢性应激可能会形成一个恶性循环，即小胶质细胞功能障碍加剧，同时Aβ积累增加，共同加剧神经退行性变。然而，令人惊讶的是，关于慢性应激是否以及如何导致小胶质细胞介导的神经炎症（这可能是AD认知障碍的基础），人们知之甚少。本综述旨在总结目前可用的临床和临床前数据，并概述将应激、小胶质细胞和神经退行性变联系起来的潜在分子机制，以促进该领域未来的研究。
