Identification of structural variations in the carboxyl terminus of Alzheimer's disease-associated beta A4[1-42] amyloid using a monoclonal antibody

The accumulation of amyloid plaques and amyloid congophilic angiopathy (ACA ) in the brains of affected individuals is one of the main pathological fea tures of Alzheimer's disease. Within these deposits, the beta A4 (A ss) pol ypeptide represents a major component with the C-terminal 39-43 amino acid variants being most abundant. Using a mouse IgG1 MoAb produced by hybridoma beta A4[35-43]-95.2 3B9, which reacts with the epitope is defined by the a mino acid residues beta A4(38)[GVV](40), this study has identified a unique conformation within the carboxyl terminus of human beta A4[1-42]. Although the beta A4(38)[GVV](40) sequence is present within the C-termini of human beta A4[1-40] and beta A4[1-43] and the beta A4-containing region of human APP, the beta A4[35-43]-95.2 3B9 MoAb (designated MoAb 3B9) does not bind these polypeptides, demonstrating a high degree of specificity for the beta A4(38)[GVV](40) epitope as presented within the beta A4[1-42] sequence. Th e beta A4[1-42] epitope bound by MoAb 3B9 is sensitive to heating (100 degr eesC for 5 min) and is denatured by SDS but not by oxidative radio-iodinati on of beta A4 or by adsorption to plastic surfaces or nitrocellulose. The r ecognition of beta A4 plaque deposits and ACA by MoAb 3B9 within formalin-f ixed sections of human AD brain demonstrates the potential of these antibod ies for investigating the role of the unique beta A4[1-42] conformation in the development of Alzheimer's disease.