Role of TGFβ signaling in the pathogenesis of Alzheimer's disease

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 beta-amyloid (A). 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 beta (TGF beta) 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 TGRi-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 TGF beta 1. Analysis in silico revealed that increased expression of receptor scavenger receptor (SR)-A, involved in A beta uptake and cell activation, by microglia exposed to TGF beta, through a Smad3-dependent mechanism could be mediated by transcriptional co-factors Smad2/3 over the MSR1 gene. We discuss that changes of TGF beta-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.