Complement and Inflammation in Pathogenesis of Dementia

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DESCRIPTION (Adapted from the application): 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, astrocytes and proteins of the complement system are associated with the senile plaques in AD brain, consistent with the hypothesis that inflammation initiated by the activation of the complement system may contribute to the generation of pathology that leads to the cognitive loss seen in this disease. 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. Nevertheless, 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 utilized to test the hypothesis that complement plays a role in the pathogenesis of AD. Potential protective effects of specific complement components in this disorder will be assessed and specific hypotheses of the protein-protein interactions that regulate these functions will be tested. Organotypic culture systems will be used to assess the ability of specific complement components to modify amyloid-induced microglial activation and its effect on neurodegeneration. Finally, the investigators will utilize Down Syndrome tissue to further assess the correlation between complement activation, inflammation and dementia. These studies should provide solid data on the significance of complement activation and inflammatory events in AD and other forms of dementia, events that could be targeted to slow the progression of the disease. Since complement has been implicated in a number of other neurodegenerative diseases, it is likely that the findings will be relevant to other diseases as well.