The Function And Mechanism Of The Interaction Between NNOS And CAPON In The A?-induced Neurotoxicity

Alzheimer's disease is a neurodegenerative disease that characterized by progressive cognitive disorder.As the world population continues to age,Alzheimer's disease has become one of the major diseases that threaten the healthy of our national population.It has become the forth disease that lead death secondly only after the heart disease,cancer and stroke.Currently,there are mainly drugs that for symptomatic treatment in clinical.They can improve and relieve symptoms to some extent,but does not cure the Alzheimer's disease.And the disease process is very long;the long-term use of these drugs will bring serious side effects.Therefore,it is important to broaden and deepen the understanding of AD pathogenesis,discovering new drug targets.The aggregation and growth of ?-amyloid is recognized as a major predisposing factor,but its neurotoxic mechanism has not been elucidated.Our present study shows the A? stimulus induces recruitment of neuronal nitric oxide synthase(nNOS)to its carboxyl-terminal PDZ ligand(CAPON).We designed a cell-permeable peptide named Tat-CAPON12c,LV-GFP-CAPONi lentivirus and ZLc-002 compounds that compete for the interaction between nNOS and CAPON.In primary neurons,Tat-CAPON12c and LV-GFP-CAPONi can significantly inhibit A?-induced cell damage,apoptosis and the atrophy of dendrites.Similary,with the use of Ap in animal models,Tat-CAPON12c and ZLc-002 can recover the deficits in learning and memory,anxiety,and behavioral abnormalities.We also found that Tat-CAPON12c can restore the expression of CREB,BDNF,Bcl-2 and Dexrasl nitrosylation due to A? stimulation.Therefore,our results suggest that inhibition of the nNOS-CAPON interaction,can reduce the activation of nNOS on Dexrasl,thereby inhibiting Dexrasl down CREB activity,thus promoting the activation of CREB and then increasing the expression of BDNF and Bcl-2.Finally,they can promote the nerve cell survival and synaptic plasticity.The nNOS-CAPON interaction and its downstream signaling pathways provide a new target for the development of drugs.And offer new opportunities for the development of more specific drugs to cure Alzheimer's disease.