ELEVATED A-BETA LEVELS IN ALZHEIMERS-DISEASE BRAIN ARE ASSOCIATED WITH SELECTIVE ACCUMULATION OF A-BETA(42) IN PARENCHYMAL AMYLOID PLAQUES AND BOTH A-BETA(40) AND A-BETA(42) IN CEREBROVASCULAR DEPOSITS

Amyloid deposits in Alzheimer's disease (AD) brains are composed prima rily of the protein A beta a proteolytic fragment of the beta-amyloid precursor protein. Antibodies were generated to peptides corresponding to the five COOH-terminal residues of A beta proteins ending either a t residue 40 (anti-A beta(36-40)) or 42 (anti-A beta(38-42)). The sele ctivity of these antibodies for their respective peptides was determin ed by antibody preabsorption followed by ELISA or immunohistochemistry . Anti-A beta(38-42) labeled core-containing and diffuse plaques in bo th frozen and paraffin sections. Anti-A beta(36-40) labeled a smaller number of core-containing plaques and no diffuse plaques. Vascular and perivascular amyloid contained A beta proteins ending both at residue 40 and 42. Forms ending at residue 40 comprised a larger fraction of both vascular and perivascular amyloid compared to parenchymal amyloid , suggesting that parenchymal amyloid and vascular/perivascular amyloi d are derived by two distinct mechanisms. In addition, A beta proteins immunoaffinity purified from plaque-enriched human brains were resolv ed by a novel electrophoretic method into two predominant forms, co-mi grating with synthetic A beta(1-40) and A beta(1-42). The quantity of A beta protein solubilized from AD brains was greater than that from a ge-matched controls, demonstrating a preferential accumulation of this soluble A beta in association with amyloid deposition. Our results de monstrate immunohistochemical and electrophoretic methods for defining further the processes contributing to A beta amyloidogenesis.