The Role of TGF-beta and Angiotensin Receptor Blockers in Modulation of Microglial Activation
Abstract
Chronic neuroinflammation is strongly associated with the development of neurodegenerative diseases such as Alzheimers and Parkinsons disease. Microglia, as the resident macrophages of the brain, are major regulators of the brains inflammatory response and are chronically activated in many neurodegenerative diseases. Chronic microglial activation occurs despite the activity of several counter regulatory anti-inflammatory signals. Regulation of chronic microglial activation through augmentation of anti-inflammatory pathways should therefore be beneficial in ameliorating neurodegeneration. However, there is some evidence that anti-inflammatory pathways are inhibited in activated microglia. In this thesis, inhibition of the anti-inflammatory TGF- signaling pathway as a potential cause of chronic microglial activation was examined. Using primary rat microglial cells we showed that the immune stimulator lipopolysaccharide (LPS) or the Alzheimers related peptide, Abeta, reduced mRNA and protein expression of the TGF- receptor, TR1 and inhibited TGF- stimulated gene expression. TGF- mediated cell death of primary microglia was also inhibited by A treatment. We showed that inhibition of the NF-B pathway, but not the MAP kinase or IRF3 pathways resulted in a reduced ability of A and LPS to restrict TGF- signaling. Therefore, A mediated inhibition of TGF- signaling could contribute to chronic microglial activation. Development of strategies that can augment the anti-inflammatory effects of TGF- signaling may be beneficial to treat neurodegenerative diseases. Anti-inflammatory drugs may be useful to reduce chronic microglial activation and hence be potential therapeutics for neurodegenerative diseases. Retrospective studiesexamining patients taking the anti-hypertensive angiotensin receptor blocker drugs (ARBs), have shown reduced incidence of Alzheimers disease compared to people taking other classes of anti-hypertensives.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 30, 2017
- Accession Number
- AD1063873
Entities
People
- Kwame O. Affram
Organizations
- Uniformed Services University of the Health Sciences