Department of Neuroscience, University of Florida, Gainesville, FL, USA.
Anatomical Institute, University of Leipzig, Leipzig, Germany.
J Alzheimers Dis. 2021;79(3):961-968. doi: 10.3233/JAD-201248.
Microglia constitute the brain's immune system and their involvement in Alzheimer's disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer's disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.
小胶质细胞构成了大脑的免疫系统，它们在阿尔茨海默病中的作用一直备受关注。通常情况下，根据淀粉样蛋白/神经炎症级联假说，小胶质细胞被描绘为潜在危险的免疫效应细胞，被认为被淀粉样蛋白过度激活，并产生神经毒性炎症介质，导致神经纤维变性。我们不同意这一理论，并提出了小胶质细胞功能障碍理论作为替代理论，该理论指出，小胶质细胞在其正常的神经保护作用中受损，因为衰老，即它们变得衰老，衰老的神经元退化，因为它们缺乏生存所需的小胶质细胞支持。因此，虽然淀粉样蛋白级联理论主要依赖于遗传数据，但功能障碍理论将衰老作为一个关键的病因因素。衰老时散发性（迟发性）和最常见的阿尔茨海默病的最大风险因素，在这种疾病中，完全外显的遗传突变不存在。在这篇综述中，我们阐述和讨论了支持衰老的小胶质细胞功能障碍的人类证据，并与淀粉样蛋白/神经炎症的观点相冲突。
