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

ABSTRACT: Among the canonical transient receptor potential (TRPC) channels, TRPC3 expression is uniquely upregulated in brains with Alzheimer’s disease (AD) based on our recent studies. Herein, we used JW-65, a selective inhibitor for TRPC3 over TRPC6, to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment completely restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their largely 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 synaptic dysfunction of AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE253510 | GEO | 2025/07/17

REPOSITORIES: GEO

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Project description:Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer’s disease (AD), however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively-intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with Aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 yrs), cognitively-intact aging (73-95 yrs) and age-matched AD cases. To identify “anti-Aging/AD” transcription patterns associated with physical activity, probesets significantly associated with both physical activity and Aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2138 probesets significant in both datasets, nearly 95% showed opposite transcription patterns with physical activity compared to Aging/AD. The majority (>70%) of these anti-Aging/AD genes showed increased expression with physical activity and decreased expression in Aging/AD. Enrichment analysis of the anti-Aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling and synaptic spine plasticity. Anti-Aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function. These data suggest that physical activity preserves a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

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

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