Sun, Zhao;
Kwon, Ji-Sun;
Ren, Yudong;
Chen, Shawei;
Walker, Courtney K;
Lu, Xinguo;
Cates, Kitra;
... Yoo, Andrew S; + view all
(2024)
Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.
Science
, 385
(6708)
, Article adl2992. 10.1126/science.adl2992.
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Abstract
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.
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