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Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models
Javier Rueda-Carrasco1, Dimitra Sokolova1,2, Sang-Eun Lee1,3
1UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
Abstract:
Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super-resolution microscopy, 3D-live imaging of co-cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aβ oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical "eat-me" signal. These apoptotic-like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aβ oligomer-induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer-TREM2 signaling in microglia-synapse engulfment in the hAPP NL-F knock-in mouse model of AD. Higher levels of apoptotic-like synapses in mice as well as humans that carry TREM2 loss-of-function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer+ synapses in Aβ-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.
Insights
Microglia engulf hyperactive synapses in early Alzheimer's disease (AD). This process, mediated by phosphatidylserine (ePtdSer) and TREM2, helps reduce synaptic hyperactivity, suggesting a protective role for microglia in AD.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuronal hyperactivity characterizes early Alzheimer's disease (AD).
- Microglia are implicated in AD pathogenesis, but mechanisms linking them to synaptic hyperactivity are unclear.
- Understanding microglia-synapse interactions is crucial for early AD intervention.
Purpose of the Study:
- To investigate the molecular mechanisms of microglia-synapse engulfment in AD.
- To determine the role of phosphatidylserine (ePtdSer) and TREM2 in this process.
- To assess the therapeutic potential of targeting microglia-synapse interactions in AD.
Main Methods:
- Super-resolution microscopy and 3D live imaging of co-cultures.
- In vivo lipid imaging in genetic models of AD.
- Analysis of TREM2 loss-of-function variants in mice and humans.
Main Results:
- Amyloid-beta (Aβ) oligomers induce synaptic hyperactivity and phosphatidylserine externalization (ePtdSer).
- Microglia engulf these "eat-me" signal-displaying spines via TREM2, reducing hyperactivity.
- Impaired ePtdSer-TREM2 signaling and increased apoptotic-like synapses observed in TREM2 variants.
Conclusions:
- Microglia actively remove hyperactive, ePtdSer-positive synapses in an Aβ-dependent manner.
- The ePtdSer-TREM2 pathway is critical for microglia-mediated synapse pruning in AD.
- Microglia may exert a beneficial role in early AD by clearing dysfunctional synapses.
