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J Biol Chem. 2004 Dec 3;279(49):50647-50. Epub 2004 Oct 13.

Identification of a new presenilin-dependent zeta-cleavage site within the transmembrane domain of amyloid precursor protein.

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  • 1Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA.

Abstract

Gamma-secretase cleavage of beta-amyloid precursor protein (APP) is crucial in the pathogenesis of Alzheimer disease, because it is the decisive step in the formation of the C terminus of beta-amyloid protein (Abeta). To better understand the molecular events involved in gamma-secretase cleavage of APP, in this study we report the identification of a new intracellular long Abeta species containing residues 1-46 (Abeta46), which led to the identification of a novel zeta-cleavage site between the known gamma- and epsilon-cleavage sites within the transmembrane domain of APP. Our data clearly demonstrate that the new zeta-cleavage is a presenilin-dependent event. It is also noted that the new zeta-cleavage site at Abeta46 is the APP717 mutation site. Furthermore, we show that the new zeta-cleavage is inhibited by gamma-secretase inhibitors known as transition state analogs but less affected by inhibitors known as non-transition state gamma-secretase inhibitors. Thus, the identification of Abeta46 establishes a system to determine the specificity or the preference of the known gamma-secretase inhibitors by examining their effects on the formation or turnover of Abeta46.

PMID:
15485850
[PubMed - indexed for MEDLINE]
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