Department of Neurology , Johns Hopkins University , Baltimore , Maryland 21287-0010 , United States.
Department of Medicine, Division of Geriatric Medicine and Gerontology , Johns Hopkins University , Baltimore , Maryland 21224 , United States.
ACS Chem Neurosci. 2019 Aug 21;10(8):3340-3342. doi: 10.1021/acschemneuro.9b00333. Epub 2019 Jun 26.
Human and animal studies suggest that inflammation occurring outside the central nervous system (systemic inflammation) may play a key role in promoting neurodegeneration, Alzheimer's disease pathology, and cognitive decline in older adults. Systemic inflammation, which is marked by increased blood levels of circulating proinflammatory cytokines and chemokines, may occur as a result of events such as infection, chronic disease, and physical and psychological stress, but may also occur outside the context of these conditions as a result of subclinical processes such as cellular senescence. Proinflammatory cytokines within the body can promote a proinflammatory environment in the central nervous system by crossing the blood-brain barrier, signaling through endothelial cells or circumventricular organs, and by stimulating the vagus nerve, which signals the detection of inflammatory proteins via direct afferent connections to the brain stem. Through each of these routes, systemic inflammation is believed to induce reactive, proinflammatory microglia and astrocytic phenotypes which can promote tau hyperphosphorylation, β-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites. Together, these molecular changes are believed initiate or exacerbate neurodegenerative processes that can eventually lead to cognitive decline and dementia in vulnerable older adults.
人体和动物研究表明，发生在中枢神经系统之外的炎症（系统性炎症）可能在促进神经退行性变、阿尔茨海默病病理和老年人认知能力下降方面发挥关键作用。系统性炎症的特征是循环促炎细胞因子和趋化因子的血液水平升高，可能是由于感染、慢性疾病以及身体和心理压力等事件引起的，但也可能由于细胞衰老等亚临床过程而在这些情况下发生。体内的促炎细胞因子可以通过血脑屏障、通过内皮细胞或室周器官信号传递，以及通过刺激迷走神经来促进中枢神经系统中的促炎环境，迷走神经通过直接传入连接到脑干来检测炎症蛋白。通过这些途径中的每一种，都认为系统性炎症会诱导反应性、促炎小胶质细胞和星形胶质细胞表型，从而促进 tau 过度磷酸化、β-淀粉样蛋白寡聚化、补体激活以及神经递质分解成潜在有害的生物活性代谢物。这些分子变化共同被认为引发或加剧神经退行性过程，最终导致脆弱的老年人认知能力下降和痴呆。
