Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models

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 A & beta; 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 A & beta; 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 A & beta;-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.

Automated summary

Neuronal hyperactivity is a key feature in early stages of Alzheimer's disease. Microglia play a potential role in disease risk, and this study found that microglia engulf apoptotic-like spines in response to Aβ oligomer stimulation, thereby reducing synaptic hyperactivity. The findings suggest a beneficial role for microglia in the earliest stages of AD.