Phospholipids are asymmetrically distributed across the plasma membrane. Phosphatidylserine (PS) is concentrated on the cytoplasmic leaflet of the lipid bilayer, but it is externalized in various situations. In the central nervous system, microglia and astrocytes recognize externalized PS on the neuronal plasma membrane. To maintain the PS asymmetry, flippases translocate PS from the exoplasmic leaflet to the cytoplasmic leaflet. Among all flippases, ATP8A1 and ATP8A2 are most abundantly expressed in the neurons in the brain. Genetic defects of ATP8A2 gene in humans cause severe disequilibrium syndrome, CAMRQ. Mice lacking ATP8A2 exhibit neurodegeneration. However, how the loss of flippases leads to neurodegeneration is not fully understood. In this study, we tried to clarify the contribution of glial engulfment via externalized PS to the neurodegeneration of ATP8A1/ATP8A2 double knock-out (DKO) mice.To clarify the contribution of glial PS receptors to neurodegeneration, genes for candidate PS receptors were knocked out in DKO mice by i-GONAD method. The number and activation states of microglia and astrocytes were analyzed by immunostaining. Neurodegeneration was analyzed by Fluoro-Jade C staining.We found neurodegeneration occurred prominently in the cerebellum of DKO mice. This neurodegeneration was improved by knocking out TREM2, a PS receptor exclusively expressed on microglia, in DKO mice. The activation of microglia was also suppressed by knocking out TREM2, suggesting that microglia activated by neuronal PS contribute to cerebellar neurodegeneration in DKO mice. Regulating the function of TREM2 and its signaling molecules may improve cerebellar neurodegeneration.