Distinctly altered TRPC3 and TRPC6 expression patterns in human Alzheimer's disease cortex and hippocampus

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Calcium dysregulation is a key factor in Alzheimer's disease (AD) neuronal damage and glial cell activation.
• Transient Receptor Potential Canonical (TRPC) channels are critical regulators of calcium signaling in the central nervous system (CNS).
• The specific changes and cellular origins of TRPC channel alterations in human AD brains are not well understood.

Purpose of the Study:

• To investigate the expression patterns and cellular localization of TRPC channels, focusing on TRPC3 and TRPC6, in human AD brain tissue.
• To compare these findings with relevant AD mouse models (5xFAD and PS19).
• To explore the relationship between TRPC channel expression and astrogliosis (reactive astrocytes).

Main Methods:

• Immunohistochemistry was performed on formalin-fixed paraffin-embedded cortical and hippocampal tissues from AD patients and age-matched controls.
• Adjacent serial sections were used to assess spatial relationships between TRPC3/TRPC6 and glial fibrillary acidic protein (GFAP)-positive astrocytes.
• Expression patterns were analyzed in 5xFAD and PS19 transgenic mouse models of AD.

Main Results:

• TRPC3 expression was significantly increased in the cortex and hippocampus of AD brains, with TRPC3-positive regions spatially correlating with reactive astrocytes.
• TRPC6 expression was significantly reduced, primarily in pyramidal neurons, and showed minimal overlap with GFAP.
• These divergent expression changes for TRPC3 and TRPC6 were consistent in both human AD samples and the studied mouse models.

Conclusions:

• Selected Transient Receptor Potential Canonical (TRPC) channels undergo differential remodeling in Alzheimer's disease pathogenesis.
• TRPC3 upregulation, potentially linked to astrogliosis, and TRPC6 downregulation in neurons are prominent and conserved alterations in AD.
• These findings highlight the role of specific TRPC channels in AD pathophysiology and suggest potential therapeutic targets.