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

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-Aβ_36–40) 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-Aβ_38–42 labeled core-containing and diffuse plaques in both frozen and paraffin sections. Anti-Aβ_36–40 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 Aβ_1–40and Aβ_1–42. 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.

Key Words:

• amyloid
• Alzheimer
• Aβ protein
• electrophoresis
• senile plaques