Browsing by Author "Valdez, Clarissa"

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    Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming
    (American Association for the Advancement of Science, 2024) Sun, Zhao; Kwon, Ji-Sun; Ren, Yudong; Chen, Shawei; Walker, Courtney K.; Lu, Xinguo; Cates, Kitra; Karahan, Hande; Sviben, Sanja; Fitzpatrick, James A. J.; Valdez, Clarissa; Houlden, Henry; Karch, Celeste M.; Bateman, Randall J.; Sato, Chihiro; Mennerick, Steven J.; Diamond, Marc I.; Kim, Jungsu; Tanzi, Rudolph E.; Holtzman, David M.; Yoo, Andrew S.; Medical and Molecular Genetics, School of Medicine
    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 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.