Abstract：
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.
摘要：
β-淀粉样蛋白（Aβ）诱导的神经元活动过度是阿尔茨海默病（AD）的早期病理特征，并有助于AD进展中的认知功能下降。然而,潜在机制尚不清楚.这里,我们发现Aβ以Ca2依赖性方式增加突触粘附分子原钙粘蛋白-γC5（Pcdh-γC5）的表达水平，与体外Aβ处理的神经元和体内APP/PS1小鼠皮质中突触的异常升高有关。通过使用Pcdhgc5基因敲除小鼠，我们证明了Pcdh-γC5在调节神经元突触形成中的关键功能，突触传递,和认知。为了进一步探讨Pcdh-γC5在AD发病中的作用,shRNA下调APP/PS1小鼠脑中Pcdh-γC5的异常表达。Pcdh-γC5的下调有效挽救了APP/PS1小鼠的神经元过度活动和认知受损。我们的发现揭示了Pcdh-γC5在介导Aβ诱导的AD神经元过度活动和认知缺陷中的病理生理作用，并确定了AD发病机制的新机制。
