NEUROGLIAL-MEDIATED IMMUNOINFLAMMATORY RESPONSES IN ALZHEIMERS-DISEASE - COMPLEMENT ACTIVATION AND THERAPEUTIC APPROACHES

Increasing evidence points to A beta-containing senile plaques as prim ary etiological agents in Alzheimer's disease (AD). The mechanism by w hich these deposits cause neurotoxicity is unresolved, but there are c ompelling data suggesting that the activated glia found associated wit h senile plaques contribute to the pathology of AD. These cells appear to release a variety of immunoinflammatory molecules, including compl ement proteins whose activation products colocalize with senile plaque s and dystrophic neurites; Previous studies showed that A beta can bin d and activate complement protein Clq, providing a plausible explanati on for the initiation of the complement cascade in AD. Data presented here further define the nature of A beta-Clq association, revealing ke y aspects of the Clq domain involved in binding the amyloid peptide. M oreover, we show that it is possible to inhibit A beta-induced complem ent activation without affecting the normal immunoglobulin-mediated co mplement pathway. This indicates that it should be feasible to develop drugs to reduce complement damage in AD without compromising this imp ortant immune-defense mechanism throughout the body.