The hallmark of AD is the formation of cerebral senile plaques, with amyloid beta protein (Abeta) as its principle component. There is ample evidence suggesting that complement activation within and around plaques leads to local inflammation and direct damage to neurons. We have discovered that Abeta specifically binds complement component C1q and activates the classical complement cascade. The intent of this proposal is to characterize the Abeta-C1q molecular association such that specific inhibitors of this interaction can be developed as potential therapeutic agents. We propose to: (1) identify the binding sites on Abeta that interact with C1q through the use of synthetic Abeta fragments in a C1q binding assay; (2) determine whether Abeta and fragments of amyloid bind C1q at the same site as the normal complement activator, immunoglobulin. This will be accomplished by testing the ability of the peptides to compete with immunoglobulin for C1q binding; and (3) develop prototype compounds that will specifically inhibit complement activation by Abeta without disrupting immunoglobulin-mediated complement activation. The further elucidation of the specific interactions resulting in complement activation by Abeta and the development of prototype inhibitors to prevent this activation could lead to the identification of therapeutic agents to slow the progression of AD.
