Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Aging Cell ; 17(1)2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29178390

RESUMEN

Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.


Asunto(s)
Axones/metabolismo , Factores de Transcripción Forkhead/metabolismo , Envejecimiento/metabolismo , Animales , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/fisiología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Noqueados , Sustancias Protectoras/metabolismo , Sustancias Protectoras/farmacología , Transducción de Señal
2.
Neurobiol Aging ; 23(1): 105-15, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11755025

RESUMEN

Both in vivo and in vitro investigations point to an important role for the immune system in the development of age-related neurodegeneration. Microglia isolated from aged female F344 rats, 18-20 months, show a higher percentage of cells with an ameboid morphology indicative of activation, whereas, astrocytes had a quiescent morphology. The ability of astrocytes and microglia to attenuate toxin-induced neuronal injury was examined. Post-natal day 1-3 pup cells optimally rescued neurons from Abeta-induced toxicity, whereas mixed glial cells from 18-20 month old rats were unable to rescue neurons from Abeta-induced toxicity. Our results suggested the appearance of a neurotoxic co-factor, therefore we investigated the basal level of nitric oxide and pro-inflammatory cytokines to determine if altered levels of immune mediators play a role in the toxicity. Mitogen-stimulated nitric oxide production increased 10 fold with age of donor, whereas, only the pup cells expressed an increase in TNF-alpha production. Basal levels of pro-inflammatory cytokines, as measured by RNA protection assays, increased with age. In particular, IL-1beta was increased 2 fold between adult and aged glial cells. The elevated cytokine expression may contribute to enhanced susceptibility to neurodegenerative diseases.


Asunto(s)
Envejecimiento/fisiología , Neuroglía/fisiología , Péptidos beta-Amiloides/toxicidad , Animales , Autorradiografía , División Celular/fisiología , Separación Celular , Células Cultivadas , Corteza Cerebral/citología , Colorantes , Citocinas/biosíntesis , Femenino , L-Lactato Deshidrogenasa/metabolismo , Neuroglía/metabolismo , Neuroglía/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Óxido Nítrico/biosíntesis , Ensayos de Protección de Nucleasas , Células PC12 , Fenotipo , Ratas , Ratas Endogámicas F344 , Estallido Respiratorio/fisiología , Factor de Necrosis Tumoral alfa/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA