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Dysfunction of the ubiquitin-proteasome pathway is a major contributing factor to proteostasis imbalance. The E3 ubiquitin ligase, F-box and WD repeat domain-containing 7 (FBXW7), a key hub factor in AD, is significantly downregulated in AD patients. FBXW7 mediates the proteasomal degradation of tau and regulates the development of tau pathology. However, the effect of FBXW7 on \u03b2-amyloid pathology and the underlying mechanisms remain unclear. This study demonstrated that FBXW7\u03b1, the dominant FBXW7 isoform, was localized in both the cytoplasm and nucleus of neurons. Aging led to a decline in FBXW7\u03b1 protein levels in the brain tissues of both wild-type and 5\u00d7FAD mice. Notably, the level of FBXW7 in the brain tissue of 5\u00d7FAD mice is significantly lower than that in wild-type mice after 6 months of age. FBXW7\u03b1 interacted with BACE1 via the conserved phosphodegron motif and targeted BACE1 for degradation. FBXW7 knockdown diminished the ubiquitination of BACE1, impaired its proteasome-mediated degradation, and increased the accumulation of BACE1 in Golgi fractions. Additionally, restoration of FBXW7\u03b1 in the hippocampus improved cognitive function and ameliorated amyloid pathology in 5\u00d7FAD mice. Our findings suggest that FBXW7\u03b1 acts as a key regulator of amyloid pathology, and highlight FBXW7\u03b1 as a promising potential therapeutic target for AD intervention.<\/jats:p>","DOI":"10.1038\/s41420-026-03159-y","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:15:20Z","timestamp":1779250520000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FBXW7\u03b1 regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"12","author":[{"given":"Yu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luping","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hewen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8340-3758","authenticated-orcid":false,"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"3159_CR1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/S1474-4422(20)30440-3","volume":"20","author":"J Graff-Radford","year":"2021","unstructured":"Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, et al. 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