Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Indiana University System; Indiana University Bloomington; Indiana University System; Indiana University Bloomington; Washington University (WUSTL); University of Texas System; University of Texas Southwestern Medical Center; University of London; University College London; Washington University (WUSTL); Washington University (WUSTL); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12447
• DOI: 10.1126/science.adl2992
• 发表日期: 2024-08-02
• 关键词: human fibroblasts; striatal neurons; tau pathology; AGE; beta; conversion; degeneration; disruption; filaments; immunity

摘要

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-beta (A beta) 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 A beta-dependent neurodegeneration, and treatment with beta- or gamma-secretase inhibitors before (but not subsequent to) A beta deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both A beta deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.