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

K Duff, C Eckman, C Zehr, X Yu, CM Prada, J Perez-Tur… - Nature, 1996 - nature.com
K Duff, C Eckman, C Zehr, X Yu, CM Prada, J Perez-Tur, M Hutton, L Buee, Y Harigaya…
Nature, 1996nature.com
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 …
Abstract
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; Mr 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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