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Letters to Nature
Nature 383, 710 - 713 (24 October 1996); doi:10.1038/383710a0

Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1

Karen Duff*, Chris Eckman, Cindy Zehr*, Xin Yu*, Cristian-Mihail Prada, Jordi Perez-tur*, Mike Hutton*, Luc Buee, Yasuo Harigaya, Debra Yager, David Morgan§, Marcia N. Gordon§, Leigh Holcomb§, Lawrence Refolo, Brenda Zenk, John Hardy* & Steven Younkin

*Suncoast Alzheimer's Disease Laboratories, University of South Florida, Tampa, Florida 33612, USA
Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
Unite 422 INSERM, Place de Verdun, 50945 Lille Cedex, France
§Alzheimer's Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, Florida 33613, USA

MUTATIONS in the genes encoding amyloid-β precursor protein (APP)1 presenilin 1 (PS1)2 and presenilin 2 (PS2)3,4 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 β-protein (βAPP) processing, which normally leads to the secretion of amyloid-β protein (relative molecular mass 4,000; M r 4K; ~90% Aβ1–40, ~10% Aβ1–42(43)), so that the extracellular concentration of Aβ42(43) is increased5. This increase in Aβ42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because Aβ42(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 Aβ42(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 Aβ42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.

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