{"doi":"10.1101/2024.09.16.611061","title":"TRPC3 suppression ameliorates synaptic dysfunctions and memory deficits in Alzheimer’s disease","abstract":"Abstract Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegeneration, such as Alzheimer’s 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 Aβ-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 β-amyloid oligomers (AβOs) induces rapid and sustained upregulation of the TRPC3 expression selectively in excitatory neurons. This aberrantly upregulated TRPC3 contributes to AβOs-induced Ca 2+ overload through the calcium entry and store-release mechanisms. The neuroprotective action of JW-65 is primarily mediated via restoring AβOs-impaired Ca 2+ /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 Ca 2+ dyshomeostasis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485244,"datarank":0.3038522435319839,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.01196572117368689,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.01196572117368689,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9459,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":415528,"name":"Chen Ling","orcid":"0000-0003-1527-1471","position":1,"is_corresponding":false},{"id":861791,"name":"Zhengjun Wang","orcid":"0000-0003-2326-4167","position":2,"is_corresponding":false},{"id":660530,"name":"Sicheng Zhang","orcid":"0000-0003-3798-7550","position":3,"is_corresponding":false},{"id":1328272,"name":"Dongyi Ding","orcid":null,"position":4,"is_corresponding":false},{"id":1085842,"name":"Lin Geng","orcid":"0000-0001-8765-8937","position":5,"is_corresponding":false},{"id":1327798,"name":"Hua Zhang","orcid":"0000-0002-5959-6473","position":6,"is_corresponding":false},{"id":1186409,"name":"Vijay K. 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