Autoantibodies to redox-modified oligomeric Aβ are attenuated in the plasma of Alzheimer's disease patients

Accumulation of A beta protein in beta-amyloid deposits is a hallmark event in Alzheimer's disease ( AD). Recent findings suggest anti-A beta autoantibodies may have a role in AD pathology. However, a consensus has yet to emerge as to whether endogenous anti-A beta autoantibodies are elevated, depressed, or unchanged in AD patients. Whereas experiments to date have used synthetic unmodified monomeric A beta (A beta(mon)) to test autoimmunity, up to 40% of the A beta pool in AD brain consists of low molecular weight oligomeric cross-linked beta-amyloid protein species ( CAPS). Recent studies also suggest that CAPS may be the primary neurotoxic agent in AD. In the present study, AD and nondemented control plasma were analyzed for immunoreactivity to CAPS and A beta(mon). Plasma of both nondemented and AD patients were found to contain autoantibodies specific for soluble CAPS. Nondemented control and AD plasmas demonstrated similar immunoreactivity to A beta(mon). In contrast, anti-CAPS antibodies in AD plasma were found to be significantly reduced compared with nondemented controls ( p = 0.018). Furthermore, age at onset for AD correlated significantly ( p = 0.041) with plasma immunoreactivity to CAPS. These data suggest that autoantibodies to CAPS are depleted in AD patients and raise the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD.