Effect Of TRPV1 On Memory Deficits And Synaptic Function In Alzheimer's Disease

Objective: Our previous report has shown that TRPV1 is involved in learning and memory and synaptic plasticity during the development of Alzheimer's disease(AD).However,whether TRPV1 contributes to AD pathogenesis and the underlying mechanism are still unclear.Methods: APP23/PS45 double transgenic mice at the age of 1.5months were microinjected with Adeno-associated virus(AAV)to overexpress or knockdown TRPV1(intra-hippocampal microinjection,1?L).1.Behavioral test: after 1.5 months,Morris water maze and Barnes maze were used to detect the spatial learning and memory.2.Western blotting: after the behavioral experiment,the brain tissues were collected to detect the expression of TRPV1,APP,BACE1,PS1,TAU-199,TAU-396,GluA1,GluA2.3.Immunohistochemistry staining: after the behavioral experiment,we collected the brain tissues for immunohistochemistry staining to the count the number of plaques.4.Electrophysiology: the patch clamp record was used to detecthippocampal CA1 LTP.5.CO-IP: CO-IP was used to detect the interaction of TRPV1 with GluA1 and GluA2.Results: Compared with wild type mice,the spatial learning and memory and hippocampal CA1 LTP were significantly impaired in APP23/PS45 mice,and the expression of TRPV1 was significantly decreased in the hippocampal tissue.Overexpression of TRPV1 dramatically improved cognitive function during Morris water maze and Barnes maze tests,and increased hippocampal LTP induction.In addition,overexpression of TRPV1 in AD mice reduces AD-related neuropathology.Finally,we found that overexpression of TRPV1 was able to enhance the interaction between TRPV1 and GluA2 subunit of AMPA receptor,and subsequently increased the synaptic level of GluA2 in AD mice.These results suggest that the TRPV1 channel may be a potential target for AD treatment.