Increased amyloid- beta 42(43) in brains of mice expressing mutant presenilin 1

• Published in: Nature (London) 1996-10, Vol.383 (6602), p.710-713
• Main Authors: Duff, K, Eckman, C, Zehr, C, Yu, Xin, Prada, C-M, Perez-Tur, J, Hutton, M, Buee, L, Harigaya, Y, Yager, D, Morgan, D, Gordon, M N, Holcomb, L, Refolo, L, Zenk, B
• Format: Article
• Language: English
• ISSN: 0028-0836
• DOI: 10.1038/383710a0

Mutations in the genes encoding amyloid- beta precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid beta -protein ( beta APP) processing, which normally leads to the secretion of amyloid- beta protein (relative molecular mass 4,000; M sub(r) 4K; similar to 90% A beta -1-40, similar to 10% A beta 1-42(43)), so that the extracellular concentration of A beta 42(43) is increased. This increase in A beta 42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because A beta 42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of A beta 42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain A beta 42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of A beta 42(43) in the brain.