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10.3390/cells14110843
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Article

Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT

by
Zhengjun Wang
1,†,
Dongyi Ding
1,†,
Jiaxing Wang
2,
Ling Chen
3,
Qingming Dong
1,
Moumita Khamrai
1,
Yuyang Zhou
1,
Akihiro Ishii
4,
Kazuko Sakata
1,
Wei Li
2,
Jianyang Du
5,
Thirumalini Vaithianathan
1,6,
Fu-Ming Zhou
1 and
Francesca-Fang Liao
1,*
1
Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
2
Department of Pharmaceutical Sciences, College of Pharmacy, 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, China
4
Department of Neuroscience, UConn Health, Farmington, CT 06030, USA
5
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
6
Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2025, 14(11), 843; https://doi.org/10.3390/cells14110843
Submission received: 3 April 2025 / Revised: 28 May 2025 / Accepted: 2 June 2025 / Published: 4 June 2025
(This article belongs to the Collection Cell Biology in the United States: Latest Advances and Perspectives)
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Abstract

To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer’s disease (AD), we challenged primary neurons with amyloid-β (Aβ). Both the naturally secreted or synthetic Aβ oligomers (AβOs) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature excitatory neurons (CaMKIIα-high) via a Ca2+-dependent calcineurin-coupled NFAT transcriptionally and calpain-mediated protein degradation, respectively. The TRPC3 expression was also found to be upregulated in pyramidal neurons of human AD brains. The selective downregulation of the Trpc6 gene induced synaptotoxicity, while no significant effect was observed from the Trpc3-targeting siRNA, suggesting potentially differential roles of TRPC3 and 6 in modulating the synaptic morphology and functions. Electrophysiological recordings of mouse hippocampal slices overexpressing TRPC3 revealed increased neuronal hyperactivity upon the TRPC3 channel activation by its agonist. Furthermore, the AβO-mediated synaptotoxicity appeared to be positively correlated with the degrees of the induced dendritic Ca2+ flux in neurons, which was completely prevented by the co-treatment with two pyrazole-based TRPC3-selective antagonists Pyr3 or Pyr10. Taken together, our findings suggest that the aberrantly upregulated TRPC3 is another ion channel critically contributing to the process of AβO-induced Ca2+ overload, neuronal hyperexcitation, and synaptotoxicity, thus representing a potential therapeutic target of AD.
Keywords: TRPC3; TRPC6; NFAT; soluble β-amyloid oligomers; excitatory neurons; neuronal hyperexcitation; Ca2+ overload; synaptotoxicity; Alzheimer’s disease TRPC3; TRPC6; NFAT; soluble β-amyloid oligomers; excitatory neurons; neuronal hyperexcitation; Ca2+ overload; synaptotoxicity; Alzheimer’s disease

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MDPI and ACS Style

Wang, Z.; Ding, D.; Wang, J.; Chen, L.; Dong, Q.; Khamrai, M.; Zhou, Y.; Ishii, A.; Sakata, K.; Li, W.; et al. Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT. Cells 2025, 14, 843. https://doi.org/10.3390/cells14110843

AMA Style

Wang Z, Ding D, Wang J, Chen L, Dong Q, Khamrai M, Zhou Y, Ishii A, Sakata K, Li W, et al. Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT. Cells. 2025; 14(11):843. https://doi.org/10.3390/cells14110843

Chicago/Turabian Style

Wang, Zhengjun, Dongyi Ding, Jiaxing Wang, Ling Chen, Qingming Dong, Moumita Khamrai, Yuyang Zhou, Akihiro Ishii, Kazuko Sakata, Wei Li, and et al. 2025. "Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT" Cells 14, no. 11: 843. https://doi.org/10.3390/cells14110843

APA Style

Wang, Z., Ding, D., Wang, J., Chen, L., Dong, Q., Khamrai, M., Zhou, Y., Ishii, A., Sakata, K., Li, W., Du, J., Vaithianathan, T., Zhou, F.-M., & Liao, F.-F. (2025). Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT. Cells, 14(11), 843. https://doi.org/10.3390/cells14110843

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