Circular RNA circTrpc6-induced tau phosphorylation contributes to neuronal injury and cognitive decline via miR-485-5p/eIF4E axis in senescence-accelerated mouse prone 8 mice

Tau hyperphosphorylation, a key neuropathological feature in neurodegenerative disorders, is strongly linked to cognitive decline. CircRNAs are recognized to play a crucial regulatory role in numerous human diseases, yet their impacts on neurodegenerative diseases remain unclear. This study was aimed to characterize and analyze the contribution of circTrpc6 to neurodegeneration and its molecular mechanisms. We found that circTrpc6 was mainly expressed in the hippocampal and cortical regions and was a cytoplastic circRNA with high abundance in neuronal cells, and its expression was upregulated in the SAMP8 hippocampus. CircTrpc6 knockdown attenuated tau phosphorylation and aggregation in N2a cells and the SAMP8 hippocampus, alleviated hippocampal neuronal and synaptic injury and improved cognitive function of SAMP8 mice. Overexpression of circTrpc6 increased tau phosphorylation and aggregation in N2a cells. Mechanistically, circTrpc6 could modulate eIF4E and p-eIF4E expression and the interaction of eIF4E and tau mRNA via interacting with miR-485-5p and influencing miR-485-5p expression, thus regulating tau phosphorylation and aggregation and affecting cognitive function. Collectively, our work indicates a crucial role of circTrpc6 in regulating tau phosphorylation and cognitive function via miR-485-5p/eIF4E axis, and implies that circTrpc6 may serve as an important regulator in tau phosphorylation and represents a potential target for treatment of cognitive decline in neurodegenerative diseases.