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

Overview

Authors: Jiaxing Wang1, Ling Chen2,3, Zhengjun Wang2, Xing-Yong Chen2,4, 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
  1. Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163 USA
  2. Department of Pharmacology, Addiction Science and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 38163 USA
  3. Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350001 P. R. China
  4. Department of Neurology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, 350001 P. R. China
  5. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
  6. Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536 USA
  7. Laboratory of Molecular Neurodegeneration, Peter the Great St Petersburg State Polytechnical University, St Petersburg, Russian Federation 195251 Russia
  8. Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163 USA
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 (how the code is found and verified)
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

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Data

Datasets cited

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

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

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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