Numerous clinical trials of anti‐amyloid agents for Alzheimer’s disease (AD) were so far unsuccessful thereby challenging the validity of the amyloid hypothesis. This lack of progress has encouraged researchers to investigate alternative mechanisms in non-neuronal cells, among which microglia represent nowadays an attractive target. Microglia play a key role in the developing brain and contribute to synaptic remodeling in the mature brain. On the other hand, the intimate relationship between microglia and synapses led to the so-called synaptic stripping hypothesis, a process in which microglia selectively remove synapses from injured neurons. Synaptic stripping, along with the induction of a microglia-mediated chronic neuroinflammatory environment, promote the progressive synaptic degeneration in AD. Therefore, targeting microglia may pave the way for a new disease modifying approach. This review provides an overview of the pathophysiological roles of the microglia cells in AD and describes putative targets for pharmacological intervention. It also provides evidence for microglia-targeted strategies in preclinical AD studies and in early clinical trials.

迄今为止，许多针对阿尔茨海默病 (AD) 的抗淀粉样蛋白药物的临床试验均未成功，从而对淀粉样蛋白假说的有效性提出了挑战。这种缺乏进展鼓励研究人员研究非神经元细胞中的替代机制，其中小胶质细胞代表了当今一个有吸引力的目标。小胶质细胞在发育中的大脑中起着关键作用，并有助于成熟大脑中的突触重塑。另一方面，小胶质细胞和突触之间的密切关系导致了所谓的突触剥离假说，即小胶质细胞选择性地从受伤的神经元中去除突触的过程。突触剥离以及小胶质细胞介导的慢性神经炎症环境的诱导促进了 AD 中的进行性突触变性。所以，靶向小胶质细胞可能为新的疾病修饰方法铺平道路。本综述概述了小胶质细胞在 AD 中的病理生理作用，并描述了药物干预的推定靶点。它还为临床前 AD 研究和早期临床试验中的小胶质细胞靶向策略提供了证据。