Preclinical study reveals that circ_0004801 exacerbates tau pathology and memory loss in Alzheimer's models, highlighting the miR-7688-5p/TTBK1 axis as a therapeutic target.
Key Points
To identify circular RNAs regulating TTBK1 and determine their functional roles and molecular mechanisms in Alzheimer's disease tau hyperphosphorylation and cognitive impairment.
Analyzed hippocampal circRNA and miRNA expression profiles in 6-month-old 3×Tg-AD and wild-type control mice.
Characterized the circ_0004801/miR-7688-5p/TTBK1 regulatory axis using dual-luciferase reporter, RNA immunoprecipitation, qRT-PCR, Western blotting, and HT22 cell viability and apoptosis assays.
Assessed hippocampal tau phosphorylation and behavioral performance in mice following lentivirus-mediated circ_0004801 knockdown and TTBK1 overexpression.
Circ_0004801 was upregulated and miR-7688-5p was downregulated in 3×Tg-AD mouse hippocampi, with binding assays confirming circ_0004801 directly sponges miR-7688-5p via the Ago2 complex.
Circ_0004801 knockdown decreased TTBK1 expression and tau phosphorylation at Ser199, Ser202, and Ser396, while increasing cell viability and decreasing apoptosis in vitro.
Lentiviral silencing of circ_0004801 in vivo decreased hippocampal p-tau (Ser199) levels and improved spatial learning, memory, and object recognition, whereas TTBK1 overexpression reversed these improvements.