Presenilin 1 is required for maturation and cell surface accumulation of nicastrin

Abstract

Proteolytic processing of amyloid precursor protein generates β-amyloid (Aβ) peptides that are deposited in senile plaques in brains of aged individuals and patients with Alzheimer's disease. Presenilins (PS1 and PS2) facilitate the final step in Aβ production, the intramembranous γ-secretase cleavage of amyloid precursor protein. Biochemical and pharmacological evidence support a catalytic or accessory role for PS1 in γ-secretase cleavage, as well as a regulatory role in select membrane protein trafficking. In this report, we demonstrate that PS1 is required for maturation and cell surface accumulation of nicastrin, an integral component of the multimeric γ-secretase complex. Using kinetic labeling studies we show that in PS1-/-IPS2-/PS2-/- cells nicastrin fails to reach the medial Golgi compartment, and as a consequence, is incompletely glycosylated. Stable expression of human PS1 restores these deficiencies in PS1-/- fibroblasts. Moreover, membrane fractionation studies show co-localization of PS1 fragments with mature nicastrin. These results indicate a novel chaperone-type role for PS1 and PS2 in facilitating nicastrin maturation and transport in the early biosynthetic compartments. Our findings are consistent with PS1 influencing γ-secretase processing at multiple steps, including maturation and intracellular trafficking of substrates and component(s) of the γ-secretase complex.