biostudies-literatureSun ZNIA NIH HHSNIMH NIH HHSNINDS NIH HHSadl2992https://www.ebi.ac.uk/biostudies/studies/S-EPMC11787906biostudies-literatureUnknown385(6708)Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based 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 Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurScience (New York, N.Y.)Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.PMC11787906P30 AG066444R01 MH123748RF1 AG056296R01 AG078964R01 NS107488Houlden HSato CLu XValdez CMennerick SJRen YHoltzman DMKarahan HBateman RJKim JKwon JSSun ZCates KFitzpatrick JAJKarch CMYoo ASTanzi RESviben SDiamond MIChen SWalker CKfalseModeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based 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 Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neur2024-01-01T00:00:00Z2024 Aug2025-04-03T23:36:51.832Z2025-04-03T23:36:51.832ZS-EPMC117879063908862410.1126/science.adl2992