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Published on: December 26, 2016
An ApoE-Associated Low-Inflammatory Microglial State Emerges After Inflammatory Challenge in Alzheimer's Disease Mice
Wenwen Cai1, Xiaoli Pan1, Ting Qian2
1Department of Neurology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032, 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.
Insights
Microglia in Alzheimer's disease (AD) adopt a low-inflammatory state during challenges, characterized by mitochondrial gene expression and neurite clearance. This finding offers new insights into microglial roles in AD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) involves neuroinflammation, with microglia playing a key role.
- The precise microglial response mechanisms to inflammatory insults in AD are not fully understood.
- Existing evidence on 'primed' AD microglia is limited, particularly at the single-cell level.
Purpose of the Study:
- To investigate microglial responses to inflammatory challenges in Alzheimer's disease models.
- To characterize microglial states and their underlying mechanisms using advanced techniques.
- To elucidate the dynamic role of microglia in AD pathogenesis.
Main Methods:
- Utilized Alzheimer's disease mouse models challenged with lipopolysaccharide (LPS).
- Employed single-cell RNA sequencing to analyze microglial states.
- Integrated in vivo immunostaining and in vitro models for mechanistic insights.
Main Results:
- Microglia exhibited a low-inflammatory state following inflammatory challenge.
- Elevated expression of mitochondrial respiratory chain genes was observed in these microglia.
- This state correlated with the phagocytosis of dystrophic neurites, with apolipoprotein E implicated.
Conclusions:
- Identified a distinct microglial state in response to inflammation in AD.
- This state is linked to mitochondrial activity and clearance of neuronal debris.
- Provides novel insights into the complex and dynamic functions of microglia in Alzheimer's disease.
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