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<p>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 Ca<sup>2+</sup>/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca<sup>2+</sup> overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca<sup>2+</sup> dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Jiaxing Wang,
  • Ling Chen,
  • Zhengjun Wang,
  • Xing-Yong Chen,
  • Sicheng Zhang,
  • Dongyi Ding,
  • Yuyang Zhou,
  • Ryan Rager-Aguiar,
  • Geng Lin,
  • Hua Zhang,
  • Vijay K. Boda,
  • Tyler C. Ortyl,
  • Peter T. Nelson,
  • Ilya Bezprozvanny,
  • Fu-Ming Zhou,
  • Jianyang Du,
  • Zhongzhi Wu,
  • Wei Li,
  • Francesca-Fang Liao

摘要

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.