Role of TGFß signaling in the pathogenesis of Alzheimer's disease.
Front Cell Neurosci
; 9: 426, 2015.
Article
em En
| MEDLINE
| ID: mdl-26578886
Aging is the main risk factor for Alzheimer's disease (AD); being associated with conspicuous changes on microglia activation. Aged microglia exhibit an increased expression of cytokines, exacerbated reactivity to various stimuli, oxidative stress, and reduced phagocytosis of ß-amyloid (Aß). Whereas normal inflammation is protective, it becomes dysregulated in the presence of a persistent stimulus, or in the context of an inflammatory environment, as observed in aging. Thus, neuroinflammation can be a self-perpetuating deleterious response, becoming a source of additional injury to host cells in neurodegenerative diseases. In aged individuals, although transforming growth factor ß (TGFß) is upregulated, its canonical Smad3 signaling is greatly reduced and neuroinflammation persists. This age-related Smad3 impairment reduces protective activation while facilitating cytotoxic activation of microglia through several cellular mechanisms, potentiating microglia-mediated neurodegeneration. Here, we critically discuss the role of TGFß-Smad signaling on the cytotoxic activation of microglia and its relevance in the pathogenesis of AD. Other protective functions, such as phagocytosis, although observed in aged animals, are not further induced by inflammatory stimuli and TGFß1. Analysis in silico revealed that increased expression of receptor scavenger receptor (SR)-A, involved in Aß uptake and cell activation, by microglia exposed to TGFß, through a Smad3-dependent mechanism could be mediated by transcriptional co-factors Smad2/3 over the MSR1 gene. We discuss that changes of TGFß-mediated regulation could at least partially mediate age-associated microglia changes, and, together with other changes on inflammatory response, could result in the reduction of protective activation and the potentiation of cytotoxicity of microglia, resulting in the promotion of neurodegenerative diseases.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Front Cell Neurosci
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Chile
País de publicação:
Suíça