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 β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca2+/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented  Ca2+ overload induced by AβOs. 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.