Mechanism And Function Of Inhibiting PKC? In Blocking A? Overproduction In Alzheimer's Disease

?Objective?Alzheimer's disease(AD)is a chronic and progressive neurodegenerative disease of the central nervous system.The pathological characteristics of the disease include extracellular ?-amyloid(A?)deposition(senile plaque),intracellular neurofibrillary tangles and neuronal loss.Many researches have demonstrated that overproduction of A? leading to metabolic abnormality,oxidative stress,inflammation,synaptic plasticity impairment and apoptosis is the key pathological basis for the pathogenesis and development of AD.Protein kinase C-?(PKC?)is an important protein kinase of intracellular signal transduction,which is involved in energy metabolism,oxidative stress and apoptosis.Previous studies have implied that PKC? may participate in modulating A? production.However,up to now,the exact mechanism and function of PKC? regulating A? overproduction in AD remain unclear.Therefore,the further studies about PKC? will benefit to clarify the molecular pathogenetic mechanism of AD,and provide new target for therapeutic agents in AD treatment.?Methods?In present study,we use specific PKC? inhibitor Rottlerin,and randomly divide six-month-old male APPswe/PS1dE9(APP-PS1)transgenic AD mice and the age-matched wild-type(WT)C57BL/6 male mice into 4 groups,including WT-Vehicle group,WT-Rottlerin group,APP/PS1-Vehicle group and APP/PS1-Rottlerin group,Each group is administrated Rottlerin or Vehicle separately by intraperitoneal injection for 12 weeks.Then,we use ethological tests,immunohistochemistry and fluorescence staining methods,ELISA,PCR and western blot to investigate the mechanism and function of PKC? inhibition in regulating A? overproduction in AD mice.?Results?(1)Rottlerin specifically inhibiting PKC? can improve the spatial learning and memory impairments in AD transgenic mice.(2)Rottlerin specifically inhibiting PKC? can markedly increase the expression of synaptic related proteins PSD-95 and SYP in the brain of AD transgenic mice.(3)Rottlerin specifically inhibiting PKC? can significantly reduce A? overproduction and A? plaque deposition in the brain of AD transgenic mice.(4)Rottlerin specifically inhibiting PKC? can bloke APP amyloidogenic pathway by significantly decrease transcription and expression of key rate-limiting enzyme BACE1 in the brain of AD transgenic mice.(5)Rottlerin specifically inhibiting PKC? has no effect on non-amyloidogenic pathway and expression of related enzymes ADAM10 and PS1,nor on the expression of A? degrading enzymes IDE and NEP in the brain of AD transgenic mice.(6)Rottlerin specifically inhibiting PKC? can significantly decrease phosphorylation of I?B? and transcription factor p65 in the NF-?B pathway,causing downregulation of BACE1 transcription and expression.?Conclusion? The present study has demonstrated that specific inhibition of PKC? by Rottlerin can decrease phosphorylation of I?B? and transcription factor p65 in the NF-?B pathway,downregulate BACE1 transcription and expression and block APP amyloidogenic pathway,thereby reducing A? overproduction and deposition,rescuing spatial learning and memory impairments in APPswe/PS1dE9 transgenic AD mouse models.The results have indicated that PKC? may play an important role in modulating A? production,and specific inhibition of PKC? by Rottlerin may be a viable treatment strategy in AD.