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

Xiao-Fei He,Zhong Pei,Li-Li Li,Jing-Hui Xu,Li-Ying Zhang,Ming-Yue Li,Ge Li,Xi-Quan Hu

doi:10.1038/s41419-020-03072-x

Abstract

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.

Highlights

Alzheimer’s disease (AD) is characterized by amyloidbeta (Aβ) deposition and neurofibrillary tangle formation in brain[1]
In present study, combining a mouse model of sporadic Alzheimer’s disease (SAD) and subsequently systemic inflammation, we investigated the role of NLRP3 inflammasome in the pathological process of SAD as well as in microglial training
Time spent in the region of interest (ROI) was significantly decreased in STZ group in Cre− mice compared with that in sham group, it was further decreased in STZ + lipopolysaccharide (LPS) group, whereas increased in STZ + MCC950 group (Fig. 1B)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by amyloidbeta (Aβ) deposition and neurofibrillary tangle formation in brain[1]. Senile plaques activate microglia and drive cerebral neuroinflammation[2], neuroinflammation has been termed as the third core pathological feature in AD3. Aβ deposition precedes the development of cognitive deficits in AD by several years[4], it is important to understand the regulation of microglial response to prevent or delay the pathological process of AD. Microglia is related to phagocytosis of Aβ5, elimination of synapse[6] and immune training[7,8]. There is an urgent need to explore the regulation of microglial training, because it exacerbates AD pathology by remembering peripheral inflammation for years. Streptozotocin (STZ) induces many pathological changes associated with sporadic Alzheimer’s disease (SAD)[12]

Methods

Results

Conclusion