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

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. AbstractNeuronal 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 A β-treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By usingPcdhgc5 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 rescue d neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research