Regulation of gamma-secretase activating protein by the 5Lipoxygenase: In vitro and in vivo evidence

Jin Chu, Jian Guo Li, Nicholas E. Hoffman, Alexandra M. Stough, Muniswamy Madesh, Domenico Praticò

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer's disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer's disease.

Original languageEnglish (US)
Article number11086
JournalScientific reports
Volume5
DOIs
StatePublished - Jun 16 2015

ASJC Scopus subject areas

  • General

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