Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.
Science
; 385(6708): adl2992, 2024 Aug 02.
Article
en En
| MEDLINE
| ID: mdl-39088624
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-ß (Aß) 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 Aß-dependent neurodegeneration, and treatment with ß- or γ-secretase inhibitors before (but not subsequent to) Aß deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Aß deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
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Esferoides Celulares
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MicroARNs
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Reprogramación Celular
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Enfermedad de Alzheimer
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Fibroblastos
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Neuronas
Límite:
Humans
Idioma:
En
Revista:
Science
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos