ABSTRACT
GOPAL THINAKARAN1 and SANGRAM S.SISODIA2 1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore,
SUMMARY
Mutations in two related genes, PS1 and PS2 account for the majority of early onset cases of familial Alzheimer’s disease (FAD). PS1 and PS2 are polytopic membrane proteins which are pedominantly localized in the endoplasmic reticulum. The precise mechanism(s) by which mutations in PS predispose individuals to FAD is not clear. However, analysis of plasma of affected individuals, conditioned medium from cells expressing FAD-linked PS variants, and transgenic mice expressing mutant PS reveal that mutant PS influences β-amyloid precursor protein (APP) processing in a manner leading to the production of elevated levels of highly toxic Aβ42 peptides. The absence of marked changes in the levels of Aβ42 in mice lacking one allele of PS1 and functional rescue of the developmental abnormalities of PS1-deficient embryos by mutant PS1 suggest that mutant PS1 causes FAD not by loss of PS1 activity during aging, but rather the gain of toxic propert(ies).
