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

Overview

Authors: Jiaxing Wang¹, Ling Chen^2,3, Zhengjun Wang², Xing-Yong Chen^2,4, Sicheng Zhang¹, Dongyi Ding², Yuyang Zhou², Ryan Rager-Aguiar², Geng Lin², Hua Zhang⁵, Vijay K Boda¹, Tyler C Ortyl², Peter T Nelson⁶, Ilya Bezprozvanny⁷, Fu-Ming Zhou², Jianyang Du⁸, Zhongzhi Wu¹, Wei Li¹, Francesca-Fang Liao²

ORCID iDs: Jiaxing Wang, Zhengjun Wang, Yuyang Zhou, Tyler C Ortyl, Ilya Bezprozvanny, Jianyang Du, Francesca-Fang Liao

Institutions: University of Tennessee Health Science Center (United States); Fujian Medical University (China); Fuzhou University (China); The University of Texas Southwestern Medical Center (United States); University of Kentucky (United States); Peter the Great St. Petersburg Polytechnic University (Russia)

Journal: Molecular psychiatry, volume 31, issue 9, pages 5031-5047

Dates: received 15 September 2025; accepted 23 March 2026; published online 11 April 2026; in print 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41380-026-03592-6 · PMID 41965896 · PMCID PMC13441893 · OpenAlex W7153514968

Open access: hybrid, a free copy (OpenAlex)

Status: data only

Categories: human (organism), mouse (organism), rat (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)

Methods: Statistics, Single-unit activity, calcium imaging

Keywords: Neuroscience, Molecular biology

MeSH: Alzheimer Disease*, Memory Disorders*, Pyrazoles*, TRPC Cation Channels*, Amyloid beta-Peptides, Animals, Disease Models, Animal, Hippocampus, Humans, Long-Term Potentiation, Male, Mice, Mice, Transgenic, Neuronal Plasticity, Neurons, Rats, Synapses (* major topic)

Topic: Ion Channels and Receptors (Sensory Systems, Neuroscience), according to OpenAlex

Funding: NIMH NIH HHS (R01 MH135862, R01 MH113986); NINDS NIH HHS (R01 NS120327, R61 NS124923); NIA NIH HHS (R56 AG078337, RF1 AG058467, R01 AG049772, R01 AG071310, R01 AG072703)

Citations: not cited yet (Europe PMC); 100 references in the paper

Abstract

Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer’s disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly 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 or preventing synaptic dysfunction of AD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

geo:GSE253510 — at NCBI GEO; found in “Data availability”

Data availability

Raw and processed RNA-seq data used in this study are available at the Gene Expression Omnibus under the accessions GSE253510 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253510).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 19 authors, 2 keywords, 17 MeSH terms, 3 funders, 99 references.

Cite

This paper

Wang, J., Chen, L., Wang, Z., Chen, X.-Y., Zhang, S., Ding, D., Zhou, Y., Rager-Aguiar, R., Lin, G., Zhang, H., Boda, V. K., Ortyl, T. C., Nelson, P. T., Bezprozvanny, I., Zhou, F.-M., Du, J., Wu, Z., Li, W., & Liao, F.-F. (2026). Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models. Molecular psychiatry, 31(9), 5031-5047. https://doi.org/10.1038/s41380-026-03592-6

BibTeX

@article{wang2026pyrazole, author = {Wang, Jiaxing and Chen, Ling and Wang, Zhengjun and Chen, Xing-Yong and Zhang, Sicheng and Ding, Dongyi and Zhou, Yuyang and Rager-Aguiar, Ryan and Lin, Geng and Zhang, Hua and Boda, Vijay K and Ortyl, Tyler C and Nelson, Peter T and Bezprozvanny, Ilya and Zhou, Fu-Ming and Du, Jianyang and Wu, Zhongzhi and Li, Wei and Liao, Francesca-Fang}, title = {{Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models}}, journal = {Molecular psychiatry}, year = {2026}, month = apr, volume = {31}, number = {9}, pages = {5031--5047}, publisher = {Springer Nature}, issn = {1359-4184}, doi = {10.1038/s41380-026-03592-6}, url = {https://doi.org/10.1038/s41380-026-03592-6}, pmid = {41965896}, pmcid = {PMC13441893} }

RIS

TY - JOUR AU - Wang, Jiaxing AU - Chen, Ling AU - Wang, Zhengjun AU - Chen, Xing-Yong AU - Zhang, Sicheng AU - Ding, Dongyi AU - Zhou, Yuyang AU - Rager-Aguiar, Ryan AU - Lin, Geng AU - Zhang, Hua AU - Boda, Vijay K AU - Ortyl, Tyler C AU - Nelson, Peter T AU - Bezprozvanny, Ilya AU - Zhou, Fu-Ming AU - Du, Jianyang AU - Wu, Zhongzhi AU - Li, Wei AU - Liao, Francesca-Fang TI - Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models T2 - Molecular psychiatry J2 - Mol Psychiatry PY - 2026 DA - 2026/04/11 VL - 31 IS - 9 SP - 5031 EP - 5047 SN - 1359-4184 PB - Springer Nature DO - 10.1038/s41380-026-03592-6 UR - https://doi.org/10.1038/s41380-026-03592-6 LA - en ER -

CSL-JSON

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