Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models

Among the canonical transient receptor potential (TRPC) channels, TRPC3 expression?is uniquely upregulated in brains with Alzheimer's disease (AD) based on our recent studies. Herein, we used?JW-65, a selective inhibitor for TRPC3 over TRPC6, to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment completely restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their largely corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble ß-amyloid oligomers (AßOs), primarily via restoring the AßOs-impaired?Ca2+/calmodulin-mediated signaling pathways. JW-65?treatment also significantly prevented? Ca2+?overload induced by AßOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca2+?dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating synaptic dysfunction of AD. Overall design: Twelve-month-old 5xFAD mice were treated with 20 mg/kg JW-65 over the course of one month (3 injections per week) via intraperitoneal (i.p.) dosing.