The Amyloid β Protein Precursor Mutations Linked to Familial Alzheimer's Disease Alter Processing in a Way That Fosters Amyloid Deposition

Abstract

Younkin, S.G. The Amyloid β Protein Precursor Mutations Linked to Familial Alzheimer's Desease Alter Processing in a Way That Fosters Amyloid Deposition. Tohoku J. Exp. Med., 1994, 174 (3), 217-223 Normal processing of the amyloid β protein precursor (BAPP) results in secretion of a soluble 4 kD protein essentially identical to the amyloid β protein (Aβ) that forms insoluble fibrillar deposits in Alzheimer's disease (AD). Strong evidence that amyloid deposition plays a critical role in the development of AD has come from the identification of familial AD (FAD) kinderds in which the AD phenotype cose-gregates with mutations in the β APP gene that are located close to the NH2 or COOH end of the Aβ peptide. The location of these mutations immediately suggests that they may cause AD by altering β APP processing in a way that is amyloidogenic. In a previous study, we found that transfected cells expressing the NH2 side mutant secrete 6-fold more 4 kD Aβ than those expressing wild type β APP or COOH side mutants. We have now shown that the mutations on the COOH side of Aβ alter processing to increase secretion of the more amyloidogenic Aβ 1-42 form which constitutes only a small percentage of the total 4 kD Aβ produced. Thus our data show that all of the FAD-linked β APP mutations alter β APP processing in a way that increases the likelihood of amyloid formation. Alzheimer's disease; familial; amyloid; precursor; mutation. © 1994, Tohoku University Medical Press. All rights reserved.