28 research outputs found
Alteration of β-secretase traffic by the receptor tyrosine kinase signaling pathway – a new mechanism for regulating Alzheimer's β-amyloid production
A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface
Presenilin 1 (PSI) and presenilin 2 play a critical role in the gamma-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PSI deletion mutant (DeltaM1,2). Stable expression of DeltaM1,2 impairs gamma-secretase processing of Notch1 and delays Abeta secretion. Kinetic studies show enhanced beta-glycosylation and siallylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in AM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PSI mutant (D385A) or incubation of cells with gamma-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in DeltaM1,2 cells. Finally, expression of DeltaM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PSI's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of gamma-secretase. Collectively, our findings provide evidence that PSI regulates the glycosylation and intracellular trafficking of APP and select membrane proteins