Characterization of the pathological significance of a novel type of vascular amyloid

The amyloid Aß peptide is deposited in at least two distinct locations in AD brain:  Parenchymal plaques and vascular amyloid deposits in the wall of arterioles, where it is associated with vascular smooth muscle cell degeneration and stroke (Congophilic amyloid angiopathy, CAA).  While CAA is commonly found in AD brain, some human mutations within the Aß domain of the amyloid precursor protein (APP) cause CAA and stroke, rather than AD indicating that these diseases can occur independently. Using a conformation-dependent monoclonal antibody, M31, we have discovered a structurally unique type of Abeta deposit that is specifically associated with vessels.  This shows that a subset of the vascular amyloid is conformationally unique and raises the hypothesis that it may be associated with a unique type of pathogenesis.  The goal of this proposal is to examine the relationship of this unique vascular amyloid to AD and CAA pathogenesis and obtain preliminary data to support an NIH application with more mechanistic and translational aims.  The results of this study may lead to the development of immunological strategies to therapeutically target CAA and image its accumulation in human brain, allowing the pre-mortem diagnosis of vascular amyloidosis and the stratification of patients for human clinical trials for both AD and CAA.