TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease

Liao, F.-F.; Wang, J.; Chen, L.; Wang, Z.; Zhang, S.; Ding, D.; Lin, G.; Zhang, H.; Boda, V. K.; Kong, D.; Ortyl, T. C.; Wang, X.; Lu, L.; Bezprozvanny, I.; Du, J.; Wu, Z.; Li, W.

doi:10.1101/2024.09.16.611061

bioRxiv · 10.1101/2024.09.16.611061

TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease

Liao, F.-F.·Wang, J.·Chen, L.·Wang, Z.·Zhang, S.·Ding, D.·Lin, G.·Zhang, H.·Boda, V. K.·Kong, D.·Ortyl, T. C.·Wang, X.·Lu, L.·Bezprozvanny, I.·Du, J.·Wu, Z.·Li, W.

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Abstract

Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegeneration, such as Alzheimers disease (AD) remain elusive. Bioinformatic analysis of the published single-cell RNA-seq data collected from AD patient cohorts indicates that the Trpc3 gene is uniquely upregulated in excitatory neurons. TRPC3 expression is also upregulated in post-mortem AD brains, and in both acute and chronic mouse models of AD. Functional screening of TRPC3 antagonists resulted in a lead inhibitor JW-65, which completely rescued A{beta}-induced neurotoxicity, impaired synaptic plasticity (e.g., LTP), and learning memory in acute and chronic experimental AD models. In cultured rat hippocampal neurons, we found that treatment with soluble {beta}-amyloid oligomers (A{beta}Os) induces rapid and sustained upregulation of the TRPC3 expression selectively in excitatory neurons. This aberrantly upregulated TRPC3 contributes to A{beta}Os-induced Ca2+ overload through the calcium entry and store-release mechanisms. The neuroprotective action of JW-65 is primarily mediated via restoring A{beta}Os-impaired Ca2+/calmodulin-mediated signaling pathways, including calmodulin kinases CaMKII/IV and calcineurin (CaN). The synaptic protective mechanism via TRPC3 inhibition was further supported by hippocampal RNA-seq data from the symptomatic 5xFAD mice after chronic treatment with JW-65. Overall, these findings not only validate TRPC3 as a novel therapeutic target for treating synaptic dysfunction of AD but most importantly, disclose a distinct role of upregulated TRPC3 in AD pathogenesis in mediating Ca2+ dyshomeostasis.

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Liao, F.-F., Wang, J., Chen, L., Wang, Z., Zhang, S., Ding, D., Lin, G., Zhang, H., Boda, V. K., Kong, D., Ortyl, T. C., Wang, X., Lu, L., Bezprozvanny, I., Du, J., Wu, Z., Li, W.. 2024-09-16. TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease. https://doi.org/10.1101/2024.09.16.611061

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