Cell adhesion molecule protocadherin-γC5 ameliorates Aβ plaque pathogenesis by modulating astrocyte function in Alzheimer’s disease

Accumulation of astrocytes around β-amyloid (Aβ) plaques is one of the earliest neuropathological changes in Alzheimer’s disease (AD), but the underlying mechanisms and significance remain unclear. Cell adhesion molecule protocadherin-γC5 (Pcdh-γC5) has been reported to implicate in AD. Here we find elevated expression level of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes, and further reveal that Pcdh-γC5 deficiency leads to exacerbated Aβ deposition in 5×FAD mice. Deletion of Pcdh-γC5 impairs astrocyte migration, astrocytic response to Aβ signaling and Aβ phagocytosis in both cultured astrocytes in vitro and 5×FAD mice in vivo. Both male and female mice were used in this study. Our findings support a model in which increased expression level of Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling, engulf and phagocytose neurotoxic Aβ plaques, therefore exerting a critical neuroprotective function in AD. Significance Statement Astrocytes play a pivotal role in AD pathogenesis. Recent evidence identified Pcdh-γC5 as a potential early-stage biomarker in the CSF of AD patients. Here by using Pcdhgc5 gene knockout astrocytes, we unravel the essential function of Pcdh-γC5 in promoting astrocyte migration and Aβ phagocytosis via PI3K-Akt-actin signaling pathway. By crossing Pcdhgc5 knockout mice and 5×FAD mice, or down regulating astrocytic Pcdh-γC5 expression with shRNA, we demonstrate the neuroprotective role of Pcdh-γC5 in ameliorating Aβ plaque pathogenesis by regulating astrocyte activity. Our investigation provides new clues in clarifying the underlying mechanisms of AD pathogenesis, especially the critical role of astrocytes in AD.