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1.
PLoS Biol ; 19(6): e3001311, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34181639

RESUMO

Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Envelhecimento/metabolismo , Animais , Ciclo Celular , Proliferação de Células , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese
2.
Proc Natl Acad Sci U S A ; 117(36): 22214-22224, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32848054

RESUMO

Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked ß-N-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the STAT3 signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of STAT3 O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.


Assuntos
Envelhecimento/fisiologia , Diferenciação Celular/fisiologia , Glucosamina/análogos & derivados , Células-Tronco Neurais/fisiologia , Neuroglia/fisiologia , Fator de Transcrição STAT3/metabolismo , Animais , Proliferação de Células , Biologia Computacional , Regulação da Expressão Gênica , Glucosamina/metabolismo , Hipocampo/citologia , Camundongos , Neurogênese , Fator de Transcrição STAT3/genética , Análise de Sequência de RNA
3.
Cell Metab ; 30(6): 1004-1006, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801054

RESUMO

Remyelination declines in the aging central nervous system due to oligodendrocyte precursor cell (OPC) dysfunction. In the latest issue of Cell Stem Cell, Neumann et al. (2019) demonstrate that aged OPCs are amenable to functional rejuvenation by systemic interventions involving alternate-day fasting or treatment with the fasting mimetic metformin.


Assuntos
Metformina , Remielinização , Diferenciação Celular , Dieta , Oligodendroglia , Células-Tronco
4.
Curr Biol ; 29(20): 3359-3369.e4, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31588002

RESUMO

Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation.


Assuntos
Acetilglucosamina/metabolismo , Envelhecimento/fisiologia , Cognição/fisiologia , N-Acetilglucosaminiltransferases/metabolismo , Acilação , Animais , Masculino , Camundongos , Camundongos Knockout
5.
Cell Tissue Res ; 371(1): 105-113, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29124393

RESUMO

Aging results in impaired neurogenesis in the two neurogenic niches of the adult mammalian brain, the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle. While significant work has characterized intrinsic cellular changes that contribute to this decline, it is increasingly apparent that the systemic environment also represents a critical driver of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis have revealed that immune-related molecular and cellular changes in the aging systemic environment negatively regulate adult neurogenesis. Interestingly, these studies have also demonstrated that age-related decline in neurogenesis can be ameliorated by exposure to the young systemic environment. While this burgeoning field of research is increasingly garnering interest, as yet, the precise mechanisms driving either the pro-aging effects of aged blood or the rejuvenating effects of young blood remain to be thoroughly defined. Here, we review how age-related changes in blood, blood-borne factors, and peripheral immune cells contribute to the age-related decline in adult neurogenesis in the mammalian brain, and posit both direct neural stem cell and indirect neurogenic niche-mediated mechanisms.


Assuntos
Envelhecimento/fisiologia , Neurogênese/fisiologia , Adulto , Animais , Sangue/imunologia , Sangue/metabolismo , Hipocampo/fisiologia , Humanos , Ventrículos Laterais/fisiologia , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos , Modelos Animais , Neurônios/imunologia , Neurônios/metabolismo , Parabiose , Ratos
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