Synaptic Adhesion Molecule Pcdh-γC5 Mediates Synaptic Dysfunction In Alzheimer’s Disease

Synaptic dysfunction and neuronal excitatory/inhibitory synaptic imbalance have been implicated in Alzheimer’s disease pathogenesis.Although intensive studies have been focused on excitatory synaptic system,much less is known about the inhibitory synaptic dysfunction in AD.It has been reported that inhibitory synaptic function is impaired in animal models of AD and AD patients.In our previous reseach,we found that protocadherin-yC5(Pcdh-yC5)can interact with GABAA receptors,and promote the expression of GABAA receptors on cell membrane,therefore regulating the GABAergic inhibitory synaptic function.In this current study,by using APP/PS1 transgenic AD mouse model and multiple techniques,we hope to further investigate the role of pcdh-yC5 in synaptic function and AD pathology.We found that in the cortex of APP/PS1 mice,the expression level of Pcdh-γC5 increased significantly,and commonly colocalized with inhibitory synaptic markers vGAT and GAD around Aβplaques.By using electrophysiological recording,it was found that the neuronal excitability and synaptic function in APP/PS1 mouse increased abnormaly,while could be rescued by knocking down the expression level of Pcdh-γC5.In addition,Aβtreatment in neurons could dose-dependently and time-dependently increase the expression of Pcdh-γC5 directly.All these results indicate that Pcdh-γC5 might play important roles in AD pathogenesis by regulating synaptic function.This study provides valuable clues in investigating the complex mechanisms of AD,and hopefully will provide potential target in AD diagnosis and treatment in the future.