Inhibition of B-Amyloid-Induced Complement Activation

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 andaround plaques leads to local inflammation and direct damage to neurons. We have discovered thatAbeta specifically binds complement component C1q and activates the classical complement cascade.Our intent is to characterize the Abeta-C1q molecular association such that specific inhibitors of thisinteraction can be developed as potential therapeutic agents. We will (1) identify the binding sites onAbeta 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 complementactivator, immunoglobulin. This will be accomplished by testing the ability of the peptides to competewith munoglobulin for C1q binding; and (3) develop prototype compounds that will specifically inhibitcomplement activation by Abeta without disrupting immunoglobulin-mediated complement activation.The further elucidation of the specific interactions resulting in complement activation by Abeta and thedevelopment of prototype inhibitors to prevent this activation could lead to the identification oftherapeutic agents to slow the progression of AD.