{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T10:46:46Z","timestamp":1792579606976,"version":"4.5.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":281,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Research and Innovation Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leverhulme Trust Project Grant","award":["RPG-2020-369"],"award-info":[{"award-number":["RPG-2020-369"]}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUK-PG2023B-003"],"award-info":[{"award-number":["ARUK-PG2023B-003"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Race Against Dementia"},{"name":"Wellcome Trust Integrative Neuroscience PhD Studentship"},{"DOI":"10.13039\/501100000268","name":"UK Research and Innovation Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022431","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022431","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genome-wide association studies have identified multiple loci that contribute to late-onset Alzheimer\u2019s disease risk, yet the functional mechanisms of many candidate genes remain unclear. WW-domain containing oxidoreductase (WWOX) is one such gene associated with disease and downregulated in patient brains, but its role in neurodegeneration is poorly understood. Here, we use Drosophila models to investigate the cell-type-specific and mechanistic roles of Wwox in ageing and amyloid-\u03b242 (A\u03b242)-induced pathology. Neuronal and glial knockdown of Wwox reduced lifespan and increased sleep drive, indicating a role in brain homeostasis. In an A\u03b242 transgenic model, neuronal Wwox knockdown exacerbated toxicity, shortening lifespan, impairing locomotion, and increasing soluble A\u03b242 levels. Transcriptomic and metabolomic analyses revealed that Wwox knockdown in an A\u03b242 transgenic model promotes metabolic reprogramming, characterized by elevated lactate dehydrogenase (Ldh) expression and increased lactate levels, driven by activation of the stress-responsive transcription factor Atf4. Genetic reduction of Ldh rescued locomotor deficits, identifying dysregulated pyruvate metabolism as a key mediator of Wwox-dependent neurotoxicity. Conversely, overexpression of Wwox in neurons markedly reduced amyloid burden, improved survival and locomotor function, and reversed A\u03b242-induced transcriptional changes. Both A\u03b242 and the protective effects of Wwox were associated with altered amino acid metabolism, including changes in the cysteine and L-methionine pathway. Together, these findings identify WWOX as a regulator of neuronal metabolic state, linking genetic risk to amyloid pathology via metabolic reprogramming, and highlight WWOX activation as a potential therapeutic strategy in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag385","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:43:30Z","timestamp":1791459810000},"source":"Crossref","is-referenced-by-count":0,"title":["Alzheimer\u2019s disease risk gene\n                    <i>Wwox<\/i>\n                    controls amyloid pathology through metabolic reprogramming"],"prefix":"10.1093","volume":"8","author":[{"given":"Hannah J","family":"Lucas-Clarke","sequence":"first","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ ,","place":["UK"]},{"name":"UK Dementia Research Institute at Cardiff University , School of Medicine, Cardiff CF24 4HQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C","family":"Maddison","sequence":"additional","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ ,","place":["UK"]},{"name":"UK Dementia Research Institute at Cardiff University , School of Medicine, Cardiff CF24 4HQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Amadio","sequence":"additional","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ ,","place":["UK"]},{"name":"UK Dementia Research Institute at Cardiff University , School of Medicine, Cardiff CF24 4HQ ,","place":["UK"]},{"name":"School of Biosciences, Cardiff University , Cardiff CF10 3AX ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Buhl","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol , Bristol BS8 1QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement","family":"Regnault","sequence":"additional","affiliation":[{"name":"College of Medical Veterinary Life Sciences, University of Glasgow Shared Research Facilities, , Glasgow G12 8QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6824-0663","authenticated-orcid":false,"given":"Owen M","family":"Peters","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at Cardiff University , School of Medicine, Cardiff CF24 4HQ ,","place":["UK"]},{"name":"School of Biosciences, Cardiff University , Cardiff CF10 3AX ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J L","family":"Hodge","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol , Bristol BS8 1QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4332-8383","authenticated-orcid":false,"given":"Gaynor A","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University , Cardiff CF24 4HQ ,","place":["UK"]},{"name":"UK Dementia Research Institute at Cardiff University , School of Medicine, Cardiff CF24 4HQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"2026102106372229600_fcag385-B1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.conb.2019.11.024","article-title":"Genetics of Alzheimer\u2019s disease: Where we are, and where we are going","volume":"61","author":"Bellenguez","year":"2020","journal-title":"Curr Opin Neurobiol"},{"issue":"3","key":"2026102106372229600_fcag385-B2","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat Genet"},{"issue":"1","key":"2026102106372229600_fcag385-B3","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41398-021-01373-z","article-title":"Cell-type-specific 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