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

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• The role of Transient Receptor Potential Canonical (TRPC) channels in neurodegenerative diseases like Alzheimer's disease (AD) is not well understood.
• TRPC3 channels are known to be expressed in the brain, but their specific involvement in AD pathogenesis requires further investigation.

Purpose of the Study:

• To investigate the role of TRPC3 channels in Alzheimer's disease.
• To evaluate the therapeutic potential of a selective TRPC3 inhibitor (JW-65) in AD models.

Main Methods:

• Examined TRPC3 expression in AD brains.
• Utilized acute and chronic experimental AD models, including 5XFAD transgenic mice.
• Assessed synaptic plasticity and learning/memory functions.
• Performed hippocampal RNA sequencing (RNA-seq) analysis.
• Tested synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs).
• Analyzed Ca2+/calmodulin-mediated signaling pathways and Ca2+ overload.

Main Results:

• TRPC3 expression was found to be upregulated in excitatory neurons of AD brains.
• JW-65 treatment significantly restored impaired synaptic plasticity and learning/memory in AD models.
• In symptomatic 5XFAD mice, JW-65 reversed impaired long-term potentiation (LTP) and corrected synaptic gene expression.
• JW-65 protected hippocampal neurons from AβOs by restoring Ca2+/calmodulin signaling and preventing Ca2+ overload.

Conclusions:

• Aberrantly upregulated TRPC3 channels contribute significantly to calcium (Ca2+) dyshomeostasis in Alzheimer's disease.
• TRPC3 represents a potential therapeutic target for preventing or treating synaptic dysfunction associated with AD.