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- W2055700087 abstract "Neuronal 5-Lipoxygenase (5LO) is an enzyme widely distributed in the central nervous system, where its expression levels are significantly increased in Alzheimer's disease (AD). Previously, we reported that genetic deficiency of 5LO results in a significant reduction of amyloid beta (Aβ) levels and deposition in a mouse model of AD. However, the mechanism responsible for this effect is not fully elucidated. In the present studies, we sought to characterize the molecular mechanism whereby 5LO modulates Aβ formation. Cells stably over-expressing human APP Swedish mutant were transfected with human 5LO cDNA, supernatants and cell lysates were collected for Aβ levels and APP metabolism, respectively. Compared with empty vector, we found that cells receiving the cDNA had a dose-dependent increase in the amount of 5LO protein levels, which was associated with a significant increase in Aβ formation. While no difference between controls and transfected cells was observed for APP, beta-secretase, alpha-secretase protein levels, a significant increase in the four components of the gamma-secretase complex, i.e. presinilin-1, nicastrin, Pen-2 and APH-1 protein, was observed. Quantitative real time PCR showed that their mRNA levels were also significantly increased. By contrast, no effect on Notch cleavage was found. Pharmacologic blockade of gamma-secretase activity completely prevented the 5LO-mediated effect, whereas a beta-secretase inhibitor did not. Similar results were obtained when specific metabolites of the 5LO enzyme (5HPETE, 5HETE) were incubated with the same cells. Further, addition of zileuton, a specific and selective 5LO inhibitor, dose-dependently reduced the amount of Aβ formation without affecting the steady state levels of APP, beta- and alpha-secretase protein. By contrast, compared with controls, cells incubated with the 5LO inhibitor had a significant reduction in all four proteins of the gamma-secretase complex. Taken together, these data support the novel hypothesis that 5LO regulates Aβ formation by directly modulating the translation of the four proteins component of the gamma secretase complex, without affecting the Notch signaling. Our work suggests that selective pharmacological inhibitors of 5LO, by acting as gamma secretase modulators, could provide a novel therapeutic opportunity for AD." @default.
- W2055700087 created "2016-06-24" @default.
- W2055700087 creator A5066538322 @default.
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- W2055700087 date "2009-07-01" @default.
- W2055700087 modified "2023-10-18" @default.
- W2055700087 title "O1-06-08: The Neuronal 5-lipoxygenase Enzymatic Pathway as a Novel Endogenous Modulator of the Gamma-secretase Complex" @default.
- W2055700087 doi "https://doi.org/10.1016/j.jalz.2009.07.126" @default.
- W2055700087 hasPublicationYear "2009" @default.
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