A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing.

Abstract:

:Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Weidemann A,Eggert S,Reinhard FB,Vogel M,Paliga K,Baier G,Masters CL,Beyreuther K,Evin G

doi

10.1021/bi015794o

subject

Has Abstract

pub_date

2002-02-26 00:00:00

pages

2825-35

issue

8

eissn

0006-2960

issn

1520-4995

pii

bi015794o

journal_volume

41

pub_type

杂志文章