School of Pharmacy, Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
Department of Physiology and Pharmacology "V.Erspamer", Sapienza University of Rome, Rome, Italy; Laboratory Pharmacology of Synaptic Plasticity, European Brain Research (EBRI) Institute, Rome, Italy.
Pharmacol Res. 2022 Oct;184:106404. doi: 10.1016/j.phrs.2022.106404. Epub 2022 Aug 18.
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.
目前，针对阿尔茨海默病（AD）的抗淀粉样蛋白药物的大量临床试验都以失败告终，这对淀粉样蛋白假说的有效性提出了挑战。这一进展的缺乏促使研究人员在非神经元细胞中探索替代机制，其中小胶质细胞是目前一个很有吸引力的靶点。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夺假说，即小胶质细胞选择性地从受损神经元中去除突触。突触剥夺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 中的进行性突触退化。因此，靶向小胶质细胞可能为新的疾病修饰方法铺平道路。本文综述了小胶质细胞在 AD 中的病理生理作用，并描述了潜在的药物干预靶点。它还为 AD 的临床前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。
