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

Autor:	Sun Z; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA., Kwon JS; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA., Ren Y; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA., Chen S; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA., Walker CK; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA., Lu X; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA., Cates K; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, USA., Karahan H; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Sviben S; Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, USA., Fitzpatrick JAJ; Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, USA., Valdez C; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA., Houlden H; UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Karch CM; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA., Bateman RJ; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA., Sato C; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA., Mennerick SJ; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA., Diamond MI; Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA., Kim J; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Tanzi RE; Genetics 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., Holtzman DM; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA., Yoo AS; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	Science (New York, N.Y.) [Science] 2024 Aug 02; Vol. 385 (6708), pp. adl2992. Date of Electronic Publication: 2024 Aug 02.
DOI:	10.1126/science.adl2992
Abstrakt:	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.
Databáze:	MEDLINE
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