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.

中文翻译：

---

小胶质细胞在散发性阿尔茨海默病中的作用

小胶质细胞构成大脑的免疫系统，并且已经讨论了它们与阿尔茨海默病的关系。通常，与淀粉样蛋白/神经炎症级联假说一致，小胶质细胞被描述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导致神经原纤维变性的神经毒性炎症介质。我们不同意这一理论，并提供小胶质细胞功能障碍理论作为替代方案，该理论指出小胶质细胞由于衰老而在其正常的神经保护作用中受损，即，它们变得衰老和老化的神经元退化，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。衰老是散发性（迟发性）和最常见阿尔茨海默病形式的最大风险因素，其中不存在完全外显性基因突变。在这篇综述中，我们列出并讨论了支持衰老小胶质细胞功能障碍和与淀粉样蛋白/神经炎症观点相冲突的人类证据。