Synaptic adhesion molecule protocadherin‐γC5 mediates β‐amyloid‐induced neuronal hyperactivity and cognitive deficits in Alzheimer's disease

• Published in: Journal of neurochemistry 2024-06, Vol.168 (6), p.1060-1079
• Main Authors: Su, Min, Xuan, Erying, Sun, Xiangyi, Pan, Gaojie, Li, Dandan, Zheng, Honghua, Zhang, Yun‐wu, Li, Yanfang
• Format: Article
• Language: English
• Subjects: Adhesion; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Cadherin Related Proteins; Cadherins - genetics; Cadherins - metabolism; Calcium ions; Cells, Cultured; Cognition; Cognition & reasoning; Cognition Disorders - metabolism; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Hyperactivity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurodegenerative diseases; neuronal hyperactivity; Neurons - metabolism; Pathogenesis; Presenilin 1; Protocadherin; Synapses; Synapses - metabolism; Synapses - pathology; synaptic adhesion molecule; Synaptic transmission; Synaptogenesis; β-Amyloid
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.16066

Neuronal hyperactivity induced by β‐amyloid (Aβ) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aβ increased the expression level of synaptic adhesion molecule protocadherin‐γC5 (Pcdh‐γC5) in a Ca2+‐dependent manner, associated with aberrant elevation of synapses in both Aβ‐treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh‐γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh‐γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh‐γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh‐γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh‐γC5 in mediating Aβ‐induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis. We propose the following mechanism in Alzheimer's disease pathogenesis: β‐Amyloid (Aβ) triggers Ca2+ influx and enhanced synaptic adhesion molecule protocadherin‐γC5 (Pcdh‐γC5) expression in a Ca2+‐dependent manner. The cleaved carboxy terminal fragment (CTF) of Pcdh‐γC5 enters the nucleus, further promoting its transcription and various synaptic proteins. Sustained neuronal hyperactivity will eventually induce vesicle depletion and synaptic dysfunction in Alzheimer's disease.