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
Biochemistryjournal_title
Biochemistryauthors
Weidemann A,Eggert S,Reinhard FB,Vogel M,Paliga K,Baier G,Masters CL,Beyreuther K,Evin Gdoi
10.1021/bi015794osubject
Has Abstractpub_date
2002-02-26 00:00:00pages
2825-35issue
8eissn
0006-2960issn
1520-4995pii
bi015794ojournal_volume
41pub_type
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