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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Mertk promotes early microglial-mediated synaptic engulfment in Alzheimer's disease
Yifan Wu1,2, Yuanteng Fan3, Shisan Bao4
1School of Basic Medical Sciences, Taikang Medical School, Wuhan University, 185 Donghu Road, Wuhan, 430071, China.
Abstract:
Rationale: Synaptic deficits occur prior to the emergence of Aβ plaques and tau pathology in Alzheimer's disease (AD). Dysregulated microglia excessively prune synapses, leading to synaptic loss. While microglia phagocytic receptor Mertk participates in synaptic pruning, the role of Mertk in driving early synaptic loss in AD remains elusive. Methods: Single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptional changes of microglia in early stage of AD mice. Mertk-mediated synaptic engulfment was investigated both in vivo and in vitro. Results: Phagocytic-associated microglia with upregulated Mertk were identified in the early stage of AD mice. Dysregulated synaptic pruning by microglia caused hippocampal synaptic loss and memory deficits in two AD mouse models. Notably, Mertk knockout or antagonist treatment reversed excessive synapse elimination by microglia. Mechanistically, Aβo-induced PPARγ promoted Mertk transcription, mediating microglial phagocytosis of synapses. Conclusions: Collectively, our findings suggest that PPARγ-regulated, Mertk-mediated microglial synaptic engulfment contributes to early synaptic loss in AD, highlighting microglial Mertk as a potential therapeutic target for AD.
Insights
Microglia excessively prune synapses in early Alzheimer's disease (AD). Upregulated Mertk drives this synaptic loss, suggesting Mertk as a therapeutic target for AD.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Synaptic deficits precede hallmark pathologies in Alzheimer's disease (AD).
- Microglia, the brain's immune cells, can excessively prune synapses, contributing to neuronal dysfunction.
- The specific role of the microglial phagocytic receptor Mertk in early AD-related synaptic loss is not well understood.
Purpose of the Study:
- To investigate the role of Mertk in microglial-mediated synaptic loss during the early stages of Alzheimer's disease.
- To elucidate the molecular mechanisms by which microglia contribute to synaptic deficits in AD.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to analyze microglial transcriptional profiles in early-stage AD mouse models.
- Mertk-mediated synaptic engulfment was assessed through in vivo and in vitro experimental approaches.
Main Results:
- Phagocytic microglia with elevated Mertk expression were identified in early AD mouse models.
- Dysregulated microglial synaptic pruning led to hippocampal synaptic loss and memory impairments in AD mice.
- Mertk knockout or inhibition ameliorated excessive microglial synapse elimination.
- Amyloid-beta oligomers (Aβo) induced PPARγ, which promoted Mertk transcription and subsequent synaptic phagocytosis by microglia.
Conclusions:
- PPARγ-regulated Mertk-mediated microglial engulfment of synapses contributes to early synaptic loss in Alzheimer's disease.
- Microglial Mertk represents a promising therapeutic target for mitigating early synaptic dysfunction in AD.
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