FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on eurodegeneration may be independent of effects on Aβ

Abstract

Strong support for a primary causative role of the Aβ peptides in the development of Alzheimer's disease (AD) neurodegeneration derives from reports that presenilin familial AD (FAD) mutants alter amyloid precursor protein processing, thus increasing production of neurotoxic Aβ 1-42 (Aβ 42). This effect of FAD mutants is also reflected in an increased ratio of peptides Aβ 42 over Aβ 1-40 (Aβ 40). In the present study, we show that several presenilin 1 FAD mutants failed to increase production of Aβ 42 or the Aβ 42/40 ratio. Our data suggest that the mechanism by which FAD mutations promote neurodegeneration and AD may be independent of their effects on Aβ production. © 2007 Mount Sinai School of Medicine.