期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 11, 页码 3344-3349出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1502150112
关键词
intramembrane protease; Alzheimer's disease; PSH; gamma-secretase; beta-amyloid peptide
资金
- Ministry of Science and Technology [2014ZX09507003006]
- National Natural Science Foundation of China [31130002, 31321062]
- NIH [R01AG026660, R01NS076117]
- Alzheimer Association [IIRG-12-242137]
Aberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into A beta 42, A beta 40, and A beta 38. The molar ratio of the cleavage products A beta 42 over A beta 40 by PSH is nearly identical to that by gamma-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the A beta 42/A beta 40 ratio. Structural analysis reveals association of a known gamma-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of gamma-secretase.
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