{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:39:52Z","timestamp":1791351592716,"version":"4.3.1"},"reference-count":100,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6708","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2024,8,2]]},"abstract":"<jats:p>Late-onset Alzheimer\u2019s disease (LOAD) is the most common form of Alzheimer\u2019s disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-\u03b2 (A\u03b2) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)\u2013based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit A\u03b2-dependent neurodegeneration, and treatment with \u03b2- or \u03b3-secretase inhibitors before (but not subsequent to) A\u03b2 deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both A\u03b2 deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.<\/jats:p>","DOI":"10.1126\/science.adl2992","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T13:58:55Z","timestamp":1722520735000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":76,"title":["Modeling late-onset Alzheimer\u2019s disease neuropathology via direct neuronal reprogramming"],"prefix":"10.1126","volume":"385","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0763-7963","authenticated-orcid":true,"given":"Zhao","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Sun","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4777-9325","authenticated-orcid":true,"given":"Yudong","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8019-3285","authenticated-orcid":true,"given":"Shawei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-4044","authenticated-orcid":true,"given":"Courtney K.","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8452-7608","authenticated-orcid":true,"given":"Xinguo","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-153X","authenticated-orcid":true,"given":"Kitra","family":"Cates","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA."},{"name":"Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3192-7362","authenticated-orcid":true,"given":"Hande","family":"Karahan","sequence":"additional","affiliation":[{"name":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA."},{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5918-4834","authenticated-orcid":true,"given":"Sanja","family":"Sviben","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A. 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