Clayton Kevin A, Van Enoo Alicia A, Ikezu Tsuneya
Department of Pharmacology and Experimental Therapeutics, Medical School, Boston University, Boston, MA, United States.
Department of Neurology, Medical School, Boston University, Boston, MA, United States.
Front Neurosci. 2017 Dec 12;11:680. doi: 10.3389/fnins.2017.00680. eCollection 2017.
Brain aging is central to late-onset Alzheimer's disease (LOAD), although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, and , and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.
脑老化是晚发型阿尔茨海默病（LOAD）的核心问题，尽管其在蛋白质或细胞水平发生的机制尚未完全明确。阿尔茨海默病是最常见的蛋白病，其特征在于两种独特的病理改变：老年斑和神经原纤维缠结，前者比后者更早出现积聚。衰老改变了淀粉样β肽和微管相关蛋白tau的蛋白质稳态，它们以自主和非自主方式受到调节。小胶质细胞是中枢神经系统中的常驻吞噬细胞，在蛋白质聚集体的非自主清除中起主要作用。它们的功能因衰老和神经退行性变而发生显著改变。小胶质细胞特异性基因与晚发型阿尔茨海默病的关联在遗传学上支持了这一点。在此，我们提出，对小胶质细胞的功能特性及其对蛋白病的贡献进行研究，将为阿尔茨海默病研究带来新的治疗方向。
