Sun, ZhaoKwon, Ji-SunRen, YudongChen, ShaweiWalker, Courtney K.Lu, XinguoCates, KitraKarahan, HandeSviben, SanjaFitzpatrick, James A. J.Valdez, ClarissaHoulden, HenryKarch, Celeste M.Bateman, Randall J.Sato, ChihiroMennerick, Steven J.Diamond, Marc I.Kim, JungsuTanzi, Rudolph E.Holtzman, David M.Yoo, Andrew S.2025-03-212025-03-212024Sun Z, Kwon JS, Ren Y, et al. Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming. Science. 2024;385(6708):adl2992. doi:10.1126/science.adl2992https://hdl.handle.net/1805/46434Late-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 neurons reduced both Aβ deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.en-USPublisher PolicyAlzheimer diseaseAmyloid precursor protein secretasesCellular reprogrammingFibroblastsMicroRNAsNeuronsArticle