NLRP3-dependent microglial training impaired the clearance of amyloid-beta and aggravated the cognitive decline in Alzheimer’s disease

作者：Xiaofei He, Jinghui Xu, Ge Li, Mingyue Li, Lili Li, Zhong Pei, Liying Zhang, Xiquan Hu · 发表于：Cell Death and Disease · 年份：2020 · DOI：10.1038/s41419-020-03072-x · 被引用次数：59 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Inflammasome and immune disorders、Immune cells in cancer

Alzheimer's disease (AD), the most common form of dementia, is marked by progressive cognitive decline, deposition of misfolded amyloid-β (Aβ) peptide and formation of neurofibrillary tangles. Recently, microglial training has emerged as an important contributor to neurological diseases, which augments the subsequent inflammation. However, how it affects the pathology of AD remains unknown. Here, using a mouse model of sporadic Alzheimer's disease (SAD) induced by streptozotocin injection, we demonstrated that microglial training exacerbated Aβ accumulation, neuronal loss, and cognitive impairment. In addition, we injected MCC950 to inhibit NLRP3 activation and used an inducible Cre recombinase to delete the NLRP3 gene in microglia. Inhibition or depletion of microglial NLRP3 could protect against the pathologies of SAD and abolish the effects of microglial training. Our results identified microglial training as an important modifier of neuropathology in SAD and demonstrated that activation of NLRP3 inflammasome contributed to the pathologies and microglial training in SAD. Therefore, NLRP3 could be a potential therapeutic target for SAD treatment.