The Roles And Mechanism Of BAG3 In Aging Related Synaptic Dysfunction Regulated By Cdk5

Alzheimer's disease(AD),also called senile dementia,is a kind of central nervous system denaturalization disease,the disease is hidden,the course is chronic and progressive,it is the most common type of senile dementia.The main manifestations are progressive memory disorder,cognitive impairment,personality changes and language disorders,such as neuropsychiatric symptoms,which seriously affect social,occupational and living functions.The pathogeny and pathogenesis of AD have not been elucidated.The characteristic pathological changes are neurogenic fibrous tangles formed by hyperphosphorylation of extracellular matrix and tau protein formed by amyloidosis of beta amyloid,as well as neuron loss and glial proliferation.Recent studies have found that the disorder of neuronal cell cycle plays an important role in the pathogenesis of neurodegenerative diseases.The cell cycle disorder directly causes the neuron to reenter the cell cycle and induce neuronal apoptosis,called CRND(Cycle-Related Neuronal death).The process of neuronal cell cycle apoptosis has its own characteristics.However,up to now,the mechanism of apoptosis is not clear.Aging is a natural law that will inevitably occur in the entire process of human life.It is also an inevitable and irreversible natural phenomenon.In the body's skill control system,the nervous system plays an irreplaceable role.When the body is aging,the nervous system is one of the most affected systems in the entire body system.The problem of aging of the central nervous system has always been a focus of concern in the natural sciences.When the nervous system is senescent,there will be some related characteristic changes in the body,so in-depth study of these characteristic changes and explore its specific molecular mechanisms can enable us to have a more comprehensive understanding of the aging of the nervous system.Cyclin-dependent kinase 5(Cdk5),as a member of the atypical CDK family,has shown that Cdk5 has no role in promoting normal cell cycle.In our laboratory,we first found that Cdk5 has the function of inhibiting the cell cycle of the nerve cells for the first time.Cdk5 is a proline mediated serine/threonine protein kinase,which plays an important role in the nervous system.The activation of Cdk5 is mainly dependent on the two activating factors p35 and p39 widely expressed in the nervous system.Cdk5 plays an important role in the normal physiological function of the nervous system,and Cdk5 plays an important role in the migration and differentiation of neurons,synaptic transmission,the development of axon dendrites and the survival of neurons through the phosphorylation of the serine/threonine loci of numerous substrates.In addition,under some pathological conditions,Calpain mediated p35 cutting forms p25,which can excessively activate Cdk5,induce neuronal apoptosis and synaptic dysfunction,and mediate the development of a variety of neurodegenerative diseases,suggesting that Cdk5 is likely to be an important target for the treatment of neurodegenerative diseases.Bcl-2-associated athanogene 3(BAG3)is a new substrate for the study of Cdk5,a major member of the co molecular chaperone BAG family.As a conservative protein,BAG3 participates in the regulation of a variety of important biological functions,including apoptosis,development,cytoskeleton formation,autophagy and resistance to external pressure.In addition to the high expression of cardiomyocytes and skeletal muscle cells,BAG3 is also expressed in the cerebral cortex and hippocampus in the nervous system,and in the development of the brain stem and the early development of the spinal cord.Previous studies on BAG3 mostly focused on cancer,while BAG3 had little effect on the function of the nervous system.This article focuses on the effects of Cdk5-BAG3 signaling pathway on synaptic function and cell senescence in the nervous system.After studying Cdk5 phosphorylation of BAG3,we cause changes in protein stability,resulting in the change of synaptic function related proteins and the disorder of synaptic function.In addition,aging is the most important inducer of AD,and we explore the relationship between aging and BAG3 and the relationship between AD and BAG3 to explore Cdk5 pass.The mechanism of aging induced by BAG3 in the pathogenesis of AD will further open up new directions for the prevention and drug development of neurodegenerative diseases such as AD and aging.