P1‐088: Regulation of gamma‐secretase activation protein by the 5lipoxygenase: in vitro and in vivo evidence
Jin Chu · Alzheimer s & Dementia · 2015
The 5-lipoxygenase (5LO) enzyme is increased in Alzheimer's disease (AD) brain where it modulates amyloid-β(Aβ) levels. The formation of Aβ is under the direct control of the γ-secretase complex and its activator, also known as 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. Postmortem brain tissue samples from transgenic mouse models of AD in which the 5LO pathway has been genetically or pharmacologically modulated, and neuronal cells were used to investigate the involvement of 5LO in the proteolytic processing of the GSAP-FL by generating the biologically active fragment GSAP 16kDa. In the current paper, we provide in vitro experimental evidence that 5LO acts as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, and that this biological effect is mediated by the activation of caspase-3. These results were confirmed in in vivo by using transgenic mouse models of AD in which the 5LO was modulated genetically or pharmacologically. Our studies represent the demonstration that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO. Taken together they further establish 5LO as an attractive and viable therapeutic target for AD with real disease-modifying properties.