| It is estimated that there are 5.4 million people affected by Alzheimer's disease (AD) in the United States with no approved disease modifying treatments to prevent or treat cognitive deficits. Furthermore, drugs that treat symptoms are effective for only a short period of time. Recent disappointing results from anti-amyloid beta (Abeta) therapies and recent intriguing results using an anti-Abeta antibody, MABT, which enhances an anti-inflammatory phagocytic response reflects the need for further investigation of specific modulators of the inflammatory response. The complement cascade (C') is a critical effector mechanism of the innate immune system for quickly clearing pathogens and directing the adaptive immune response. The beneficial and detrimental roles of C' in AD are becoming more established as well as the relationship of C' with other aspects of inflammation (in the periphery as well as the central nervous system (CNS)) making a thorough understanding of the role of complement in the disease more critical for therapeutic design. For example, complement components have been found to synergize with other innate immune proteins, such as Toll-Like Receptors (TLRs), which are known to also interact with fibrillar amyloid in AD associated plaques. While mouse models are critical for preclinical investigation, many critical differences between the mouse and human immune system make disease modeling difficult. C5a, generated as a consequence of complement activation, is a potent pro-inflammatory mediator of the C'. Evidence is accruing that a pharmacological approach using an antagonist to CD88, a C5a receptor (C5aR), will prevent a detrimental chronic inflammatory state produced by C5a, while preserving beneficial effects of other complement components (C1q and C3b). We hypothesize that prevention of C5aR-induced damage by immune mediators to neurons surrounding the amyloid plaques will slow progression of neurodegenerative disease. In addition to testing the hypothesis directly by using a pharmacological approach I used mouse models of AD lacking C5aR (CD88) to determine if the inflammatory response is diminished and disease progression is slowed by the lack of the receptor, and used mouse models of AD overproducing the C5a protein to determine whether this accelerates disease progression. Finally, we propose the generation of a new mouse model of neuroinflammatory diseases that will have greater complement activity and more accurately reflect the activation of the complement cascade in humans.;Together, my dissertation research adds to our knowledge of the interactions between one aspect of inflammation in Alzheimer's disease. |
