Circ_0004801 promotes tau hyperphosphorylation and cognitive impairment in Alzheimer's disease through the miR-7688-5p/TTBK1 axis

BackgroundAbnormal tau hyperphosphorylation is a central feature of Alzheimer's disease (AD). Tau tubulin kinase 1 (TTBK1) is a key kinase involved in tau phosphorylation, but its upstream regulatory mechanisms remain poorly understood.ObjectiveTo identify circRNAs involved in the upstream regulation of TTBK1 and elucidate their molecular mechanisms and functional roles in tau hyperphosphorylation and cognitive impairment in AD.MethodsHippocampal circRNA and miRNA profiles were analyzed in 6-month-old 3×Tg-AD and wild-type mice. The candidate regulatory axis was investigated using qRT-PCR, Western blotting, dual-luciferase reporter and RNA immunoprecipitation assays, cell viability and apoptosis analyses, lentiviral intervention, immunofluorescence, silver staining, and behavioral tests.ResultsCirc_0004801 was upregulated and miR-7688-5p was downregulated in the hippocampus of 3×Tg-AD mice. Circ_0004801 knockdown enhanced HT22 cell viability, reduced apoptosis, decreased TTBK1 expression, and suppressed tau phosphorylation at Ser199, Ser202, and Ser396. MiR-7688-5p overexpression reduced TTBK1 expression and tau phosphorylation at Ser199 and Ser202, whereas TTBK1 overexpression reversed these effects. Reporter and RNA immunoprecipitation assays supported a sequence-dependent interaction between circ_0004801 and miR-7688-5p and their association with the Ago2 complex. In vivo, circ_0004801 knockdown reduced hippocampal p-tau (Ser199) and improved spatial learning, memory, and object recognition, whereas TTBK1 overexpression attenuated these benefits.ConclusionsCirc_0004801 acts as an upstream regulator of TTBK1 by sequestering miR-7688-5p, thereby promoting tau hyperphosphorylation and cognitive impairment in AD. This axis may represent a potential target for tau-directed intervention.