COMPLEMENT MECHANISMS IN AMYLOID BETA PEPTIDE CLEARANCE

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DESCRIPTION (provided by applicant): Inflammation is a mixture of destructive and rebuilding forces, the balance of which dictates the overall utility or loss to the organism. By understanding which inflammatory mechanisms are useful in Alzheimer's disease (AD) and which are detrimental, we may arrive at better ways of treating the disorder. Our previous AD inflammation research under the present RO1 has emphasized toxicity mechanisms. Here, we focus on a potentially beneficial mechanism of AD inflammation, complement opsonization of amyloid beta peptide (Abeta), and how it may play a critical role in both CNS and peripheral processing of Abeta. Specific Aim 1 will use cultures of AD microglia to investigate complement mechanisms in the clearance of brain Abeta, and hAPP overexpressing transgenic mice crossed with C3-knockout mice to evaluate the operation of those mechanisms in vivo. We will show that complement opsonins and anaphylatoxins help drive microglial chemotaxis to and phagocytosis of Abeta, and that, in their absence, brain accumulation of Abeta increases. Since complement opsonization is a normal feature of antibody-mediated clearance of antigens, the studies will also investigate complement interactions with Abeta immunization. Specific Aim 2 will extend the findings to peripheral Abeta clearance. Recent studies have shown that peripheral pools of Abeta exist, and that an anti-Abeta antibody that does not materially penetrate the brain sequesters or removes circulating Abeta, resulting in decreased brain Abeta deposition. The critical question then becomes, what happens to the Abeta? Complement mechanisms in clearance of circulating immune complexes are well known, and we expect to demonstrate that they are operative in the context of peripheral Abeta clearance. Crosses of hAPP-overexpressing with C3- knockout mice should show peripheral as well as CNS deficits in Abeta removal. Abeta accumulation due to deficient complement mechanisms could engender enhanced neurodegeneration in our mouse model. Alternatively, the inhibition of complement lytic mechanisms could be neuroprotective. We will compare peripheral complement and Abeta measures with measures of neurodegeneration to evaluate whether, on balance, complement mechanisms are ultimately more helpful than harmful in AD. The studies will also examine interactions of complement deficiency with Abeta immunization, which could cause immune complex deposition problems that may be relevant to current clinical trials.