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

Affiliations
  • 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.

Published on:

August 1, 2024

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.