한빛사논문
- 조회524
Zhao Sun 1 2 3, Ji-Sun Kwon 1 4, Yudong Ren 1 5, Shawei Chen 1 2 3, Courtney K Walker 1 2 3, Xinguo Lu 6, Kitra Cates 1 7, Hande Karahan 8 9, Sanja Sviben 10, James A J Fitzpatrick 10, Clarissa Valdez 11, Henry Houlden 12, Celeste M Karch 3 6 13, Randall J Bateman 14 15, Chihiro Sato 14 15, Steven J Mennerick 6, Marc I Diamond 11, Jungsu Kim 8 9, Rudolph E Tanzi 16, David M Holtzman 3 13 15, Andrew S Yoo 1 2 3 *
1Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
3Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
4Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
7Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, USA.
8Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
9Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
10Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, USA.
11Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
12UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
13Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
14Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO 63110, USA.
15Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
16Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
*Corresponding author: correspondence to Andrew S Yoo
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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-02)
- 국외 연구진
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