The Effects And Mechanism Of BAG3 Mediated Attenuation On Alzheimer’s Disease Pathogenesis

Alzheimer’s disease(AD)is an irreversible major neurodegenerative disease that is closely related to aging and is caused by both environmental and genetic factors.Its pathological features are Diffuse brain atrophy,amyloid plaque deposited in brain tissue,and characteristic neurofibrillary tangles formed by highly phosphorylated tau proteins clustered together(Neurofibrillary tangle,NFT)and so on.Cyclin Dependent Kinase 5(CDK5)is a protein kinase that plays an important role in the nervous system,mainly by phosphorylating the Ser/Thr site of its substrate,in neuronal apoptosis,cell cycle,dendritic development,and neurite outgrowth.It plays an important role in the transmission of touch.The non-cyclin P35 is a major factor in determining the activity of CDK5 in the nervous system.Under many stress conditions,it can be cleaved by Calpain into a more stable P25.P25 can bind to CDK5 as a complex,making CDK5 over-activated and continuously phosphorylated.Its substrate,which in turn causes some diseases.In our laboratory,SILAC discovered a new substrate for CDK5,BAG3,which is an important member of the Bcl2-related anti-apoptotic factor BAG family.There are many reports on the role of BAG3 in the nervous system.We found that BAG3 interacts with P25 via a BAG domain,and that CDK5-mediated BAG3 phosphorylation can affect the protein stability of BAG3.Studies have shown that AD pathogenic protein Aβ can cause P25 accumulation and lead to excessive activation of CDK5.During AD pathogenesis,BAG3 is phosphorylated by CDK5 and causes its degradation.And when we overexpressed BAG3 in the hippocampal CA1 region of AD mice,we found that the synaptic protein levels of these mice were significantly increased,the electrophysiological recordings of LTP increased,and the behavioral animal behavioral results also showed BAG3 overexpression.Later,the learning and memory abilities of these AD model mice can be Rescue.Taken together,our study demonstrates that over-activated CDK5 causes BAG3 phosphorylation to promote its degradation,which in turn affects the number of synaptic proteins and synaptic function,which may be due to up-regulation of decreased synaptic protein levels in the course of AD.To come into play,these results provide new targets for the development of early therapeutic drugs for AD.