Synapse loss is one of the most critical features in Alzheimer's disease (AD) and correlates with cognitive decline. Astrocytes mediate synapse elimination through multiple EGF-like domains 10 (MEGF10) pathways in the developing and adult brain to build the precise neural connectivity. However, whether and how astrocytes mediate synapse loss in AD remains unknown. We here find that the phagocytic receptor MEGF10 of astrocytes is significantly increased in vivo and in vitro, which results in excessive engulfment of synapses by astrocytes in APP/PS1 mice. We also observe that the astrocytic lysosomal-associated membrane protein 1 (LAMP1) is significantly elevated, colocalized with the engulfed synaptic puncta in APP/PS1 mice, and astrocytic lysosomes contain more engulfed synaptic puncta in APP/PS1 mice relative to wild type mice. Together, our data provide evidence that astrocytes excessively engulf synapses in APP/PS1 mice, which is mediated by increased MEGF10 and activated lysosomes. The approach targeting synapse engulfment pathway in astrocytes would be a potent therapy for AD.
Keywords: Alzheimer’s disease; astrocytes; lysosomal-associated membrane protein 1; multiple EGF-like domains 10; synapse elimination; synapse engulfment.