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 4kD 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 cosegregates with mutations in the βAPP gene that are located close to the NH2 or COON end of the Aβ peptide. The location of these mutations immediately suggests that they may cause AD by altering βAPP 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 4kD Aβ than those expressing wild type BAPP or COON side mutants. We have now shown that the mutations on the COON side of Aβ alter processing to increase secretion of the more amyloidogenic Aβ1-42 form which constitutes only a small percentage of the total 4kD Aβ produced. Thus our data show that all of the FAD-linked βAPP mutations alter βAPP processing in a way that increases the likelihood of amyloid formation.
