Elevated Aβ levels in Alzheimer's disease brain are associated with selective accumulation of Aβ42 in parenchymal amyloid plaques and both Aβ40 and Aβ42 in cerebrovascular deposits

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Abstract
Amyloid deposits in Alzheimer's disease (AD) brains are composed primarily of the protein Aβ, a proteolytic fragment of the β-amyloid precursor protein. Antibodies were generated to peptides corresponding to the five COOH-terminal residues of Aβ proteins ending either at residue 40 (anti-Aβ36–40) or 42 (anti-Aβ 38-42). The selectivity of these antibodies for their respective peptides was determined by antibody preabsorption followed by ELISA or immunohistochemistry. Anti-Aβ38–42 labeled core-containing and diffuse plaques in both frozen and paraffin sections. Anti-Aβ36–40 labeled a smaller number of core-containing plaques and no diffuse plaques. Vascular and perivascular amyloid contained Aβ 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 amyloid are derived by two distinct mechanisms. In addition, Aβ proteins immunoaffinity purified from plaque-enriched human brains were resolved by a novel electrophoretic method into two predominant forms, co-migrating with synthetic Aβ1–40and Aβ1–42. The quantity of Aβ protein solubilized from AD brains was greater than that from age-matched controls, demonstrating a preferential accumulation of this soluble Aβ in association with amyloid deposition. Our results demonstrate immunohistochemical and electrophoretic methods for defining further the processes contributing to Aβ amyloidogenesis.

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