{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T08:38:59Z","timestamp":1793090339515,"version":"4.5.0"},"reference-count":36,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"National Innovation and Entrepreneurship Training Program for Undergraduate","award":["202510570013"],"award-info":[{"award-number":["202510570013"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Abnormal 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hippocampal circRNA and miRNA profiles were analyzed in 6-month-old 3\u00d7Tg-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Circ_0004801 was upregulated and miR-7688-5p was downregulated in the hippocampus of 3\u00d7Tg-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Circ_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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261487120","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:03:50Z","timestamp":1789135430000},"page":"211-226","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Circ_0004801 promotes tau hyperphosphorylation and cognitive impairment in Alzheimer's disease through the miR-7688-5p\/TTBK1 axis"],"prefix":"10.1177","volume":"114","author":[{"given":"Qingqing","family":"Li","sequence":"first","affiliation":[{"name":"Guangzhou Medical University"},{"name":"Guangzhou Medical University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5713-8690","authenticated-orcid":false,"given":"Jie","family":"Xiao","sequence":"additional","affiliation":[{"name":"Guangzhou Medical 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