Wenwen Cai1  · Xiaoli Pan1  · Ting Qian2  · Shiwen Yu1  · Ruoqi Zhao1  · Cuiqing Zhu3  · Shaoming Sang1,4 · Chunjiu Zhong1,3,5

1 Department of Neurology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China 

2 Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China 

3 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China 

4 Department of Neuroscience, University of Connecticut Health, Farmington, CT 06030, USA 

5 National Clinical Research Center for Aging and Medicine, Huashan Hospital, affiliated with Fudan University, Shanghai 200040, China

Abstract

Patients with Alzheimer’s disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.

Keywords

Alzheimer’s disease; Systemic inflammation; Microglia priming; Dystrophic neurites; Apolipoprotein E

[SpringerLink]