INVESTIGATION OF COMPLEMENT INDUCED NEUROTOXIC AND NEUROPROTECTIVE PATHWAYS

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Project 4: Neuroprotection and neuroinflammation induced by the complement proteins Clq and C5a The complement system is a component of the innate immune system whose function is to recognize deviations from the norm (such as an infection or tissue injury) and to initiate a response that will protect and initiate repair of the injured area. If not properly regulated however, tissue damage results. Previous observations suggest a detrimental effect of the activation of the complement cascade at a late stage of Alzheimer's disease when amyloid plaques containing the fibrillar, and thus complement activating, form of the amyloid peptide, AB, accumulate. Clq, the recognition component of one pathway of complement activation, binds to fibrillar amyloid and activates the pathway. One downstream product of complement activation is C5a which is known to enhance inflammation by binding to specific receptors. In this proposal, a C5a receptor antagonist which has proven effective in limiting complement mediated inflammation in other models, is being tested as a potential targeted therapy in AD mouse models. This point of inhibition would leave the remainder of the complement cascade intact, thereby permitting potentially beneficial effects of complement, such as enhanced clearance of abnormal (amyloid) deposits (by C3b), apoptotic cells and/or cellular debris (by Clq and C3b). However, it is also becoming increasingly evident that there are both activating and modulating/decoy receptors for C5a expressed in brain, and thus we propose to determine whether the balance of expression of these receptors dictates the degree of inflammation in the AD brain. In addition, Clq, which is known to be synthesized and secreted as a response to injury, has recently been shown to down regulate proinflammatory cytokines in peripheral macrophages and to provide survival signals to neurons in vitro. Using several in vitro approaches, the basis for these neuroprotective events will be defined. Results of these proposed studies should provide solid data on the significance of the contribution of complement-induced inflammatory events in AD and likely other neurodegenerative disease in the aging individual. Therapeutic inhibitors of detrimental processes identified here as well as reagents or treatments that promote the neuroprotective functions induced can subsequently be designed to slow the progression of this pervasive disease of the elderly.