The Role Of Microglia In Aging

Throughout our lives when inflammation occurs in the CNS microglia are activated to quickly deal with the source of inflammation much like the peripheral macrophages deal with inflammation throughout the rest of the body. Microglial cells are the resident immune cells of the CNS, which constitutively express surface receptors that trigger or amplify the innate immune response. These include complement receptors, cytokine receptors, chemokine receptors, major histocompatibility complex II, and others. In the case of cellular damage, they respond promptly by inducing a protective immune response, which consists of a transient up regulation of inflammatory molecules as well as neurotrophic factors.43 This innate immune response usually resolves potential pathogenic conditions.

It has been proposed that the increase in brain microglial activation may be one of the early events that leads to oxidative damage. Activated microglia release radicals such as superoxide and nitric oxide.44 Microglia derived radicals, as well as their reaction products hydrogen peroxide and peroxynitrite, can harm cells and these products have been shown to be involved in oxidative damage and neuronal cell death in neurological diseases.45 Microglial cells are equipped with efficient antioxidative defense mechanisms. They contain high concentrations of gluthatione, the antioxidative SOD enzymes, catalase, glutathione peroxidase, and glutathione reductase, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-regenerating enzymes.45 When the production of ROS is prolonged, the endogenous reserves of antioxidants become exhausted and result in cell damage.

It has been proposed that at least two activation states of peripheral macrophages can be identified46 and as microglia are the macrophages of the brain it is likely that these phenotypes apply to microglia as well. The state induced by TH1 cytokines such as IL-1, IL-6, TNFa, and CD40 ligand is referred to as the classical inflammation state by Duffield (2003) and Ml by others.47 This is a proinflammatory state that is associated with further production of these proinflammatory cytokines, ROS, chemokines, and matrix metalloproteases, resulting in cell death of invading cells and further inflammation. A second state of activation, the alternative activation state is associated with the TH2 cytokine profile of IL-4, IL-10, and TGF^-1.

When macrophages/microglia are in this state there is little release of proinflammatory cytokines and resistance to activation by agents such as LPS. In this alternative state macrophages promote extracellullar matrix formation and angiogenesis. Duffield (2003) suggests that a major difference between beneficial resolving inflammation and detrimental chronic inflammation is a failure to transition between classical and alternative states of activation, leading to tissue destruction and organ failure. It is possible that in the aged brain, microglia are primarily in the classical activation state as reflected by high levels of tumor necrosis factor alpha (TNFa) and other TH1 cytokines and low levels of Il-10 and other TH2 cytokines. As a result of chronic inflammation, prolonged activation of microglia triggers a release of a wide array of neurotoxic products48 and proinflammatory cytokines such as IL-1^, IL-6, TNFa. Aged brains seem to be in this state of chronic inflammation; as seen by, elevated protein levels of proinflammatory molecules such as, IL-1^, TNFa, and IL-6.29'49'50 Microglia have been attributed to some of these increases. Animal studies have shown that increased levels of IL-6 in the hippocampus and cerebral cortex are primarily from microglia.51

Patients with diseases such as AD and Parkinson's disease (PD) show signs of microglia in the chronic inflammatory state and this may be one of the predisposing factors that leads to the development of these neurodegenerative diseases.52-54

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