Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH
Abstract
Amyloid precursor protein (APP) is cleaved by β-secretase to produce APP C99, which undergoes additional, sequential cleavages by γ-secretase to generate amyloid-β peptides including Aβ40 and Aβ42. Increased ratios of Aβ42 over Aβ40 are thought to cause Alzheimer's disease. Screening of γ-secretase modulators is hindered by the technical challenges in expression and biochemical manipulation of γ-secretase. In this study, we demonstrate that the archaeal intramembrane protease PSH represents an excellent surrogate of γ-secretase in terms of cleavage of APP C99, ratio of Aβ42 over Aβ40, and modulation of cleavage preferences by known modulators of γ-secretase. Our finding may facilitate discovery of γ-secretase inhibitors and modulators.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- March 2015
- DOI:
- 10.1073/pnas.1502150112
- Bibcode:
- 2015PNAS..112.3344D