Alzheimer's disease (AD) is a common dementia or loss of cognitive abilities, which is linked to degeneration of brain tissue. The cause of this neurodegeneration is under intense investigation, as a critical step toward designing therapies for this debilitating and costly disease. In a variety of test systems, fibrillar beta-amyloid displays neurotoxic properties via its direct interaction with neurons but also via its interaction(s) with microglia and its ability to activate the complement system. Multiple studies have demonstrated that reactive microglia and astrocytes and proteins of the complement system are associated with the senile plaques in AD brain, suggesting that inflammation initiated by or exacerbated by activation of the complement system may be one of the major processes involved in the generation of pathology that leads to the cognitive loss. The complement (C') system is a powerful effector mechanism of the immune system. Tissue damage can result however, from chronic or unregulated activation of this system. However, it is also becoming increasingly evident that some complement components provide protective functions in areas of injury. Thus, in this research program novel mouse models will be generated to more closely mimic the human complement system to test the hypothesis that complement plays a role in the pathogenesis of Alzheimer's Disease. Organotypic culture systems will be used to assess the ability of specific complement components to modify amyloid-induced microglia-mediated neuronal cell death/degeneration. In addition, potential protective effects of specific complement components in this disorder will be defined and the specific ligand-receptor interactions that regulate these functions will be determined. These studies should provide solid data on the significance of complement activation and inflammatory events in AD--events which could be targeted to slow the progression of the disease, as well as develop relevant animal models for testing potential therapies in vivo. Since complement has been implicated in a number of other neurodegenerative diseases, it is likely that the investigators' findings will be relevant to other diseases as well.
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