In this proposal, we investigate the hypothesis that an inflammatory cascade contributes to the neurodegeneration that occurs in Alzheimer's disease (AD). Specifically, Abeta in a series of conformation dependent events accumulates in the aging brain and coverts an acute injury response into a chronic inflammatory cascade. In addition, we propose that a major contributing factor to this cascade is increased expression of the TNF/Fas superfamily of cytokines and receptors that occurs in the brain during normal aging. In the immune system, pro-inflammatory cytokines, such as interleukin-1 beta (IL-1beta), tumor necrosis factor (TNFalpha), and the Fas ligand (FasL) are key mediators of the inflammatory response, and TNFalpha and FasL are also instrumental in initiating apoptosis. Recent evidence, from our group and others, indicates that apoptotic-related mechanisms are occurring in the AD and this may be occurring in AD and other neurodegenerative diseases. The roles of TNFalpha and two of its receptors (TNFRI and TNFRII) in brain injury and neurodegenerative diseases have been extensively investigated. The role of the FasL and its receptor (Fas/CD95), and TNFalpha-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors in the brain has only recently begun to be studied. Several receptors have now been published that implicate these cytokines and their receptors in acute brain injury. Moreover, we believe that decreased expression of key proteins, such as TNFRII, TRAFs and inhibitors of apoptosis (i.e., FLIP and NAIP) may also be a critical element contributing to neurodegeneration and cognitive decline in AD. There are two specific hypotheses to be tested in this proposal. The first hypothesis is that some TNF/Fas superfamily receptors and cytokines increase in the aging and AD brain where they contribute to neurodegeneration. The second hypothesis is that the increase in expression of these cytokines and their receptors in the brain can be attenuated by activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma) that has been shown to have broad anti-inflammatory properties.
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