Abstract
BackgroundThe 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein, called 5-lipoxygenase activating protein. While previous works have shown that 5-lipoxygenase is involved in the pathogenesis of Alzheimer’s disease, no data are available on the role that 5-lipoxygenase activating protein plays in Alzheimer’s disease.MethodsIn the present paper, we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of Tg2576 mice.ResultsAmyloid β peptide (Aβ) deposition in the brains of mice receiving MK-591, a selective and specific 5-lipoxygenase activating protein inhibitor, was significantly reduced when compared with controls. This reduction was associated with a similar decrease in brain Aβ peptides levels. MK-591 treatment did not induce any change in the steady-state levels of amyloid-β precursor protein, β-site amyloid precursor protein cleaving enzyme 1 or disintegrin and metalloproteinase domain-containing protein 10. By contrast, it resulted in a significant reduction of the γ-secretase complex, at the protein and message level. Furthermore, in vitro studies confirmed that MK-591 prevents Aβ formation by modulating γ-secretase complex levels without affecting Notch signaling.ConclusionsThese data establish a novel functional role for 5-lipoxygenase activating protein in the pathogenesis of Alzheimer’s disease-like amyloidosis, and suggest that its pharmacological inhibition could provide a novel therapeutic opportunity for Alzheimer’s disease.
Highlights
The 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein, called 5-lipoxygenase activating protein
In vivo studies 5-lipoxygenase activating protein blockade reduces brain Amyloid β peptide (Aβ) peptides levels and deposition Starting at 7 months of age, Tg2576 mice were randomized to receive MK-591 (320 mg/kg diet) or vehicle in their chow diet for 8 months before being killed
Extractable) and insoluble (FA extractable) Aβ1-40 and Aβ1-42 in their cerebral cortex as well as hippocampus, the levels of which were significantly reduced in mice receiving MK-591 (Figure 1A-D)
Summary
The 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein, called 5-lipoxygenase activating protein. The enzyme 5-lipoxygenase (5LO) catalyzes the conversion of arachidonic acid to 5-hydroxyperoxyeicosatetraenoic acid and subsequently to 5-hydroxyeicosatetraenoic acid, which can be metabolized into different leukotrienes [1] It is abundantly present in the central nervous system (CNS), where its activity is regulated by the presence and availability of another protein, 5LO-activating protein (FLAP) [2]. Recent studies showed that hippocampi from patients with Alzheimer’s disease (AD) have higher 5LO immunoreactivity when compared with healthy controls, and that the genetic absence of 5LO results in a significant reduction of the brain amyloidotic phenotype of amyloid-β precursor protein (APP) transgenic mice (that is, Tg2576) [4,5] Taken together, these data suggest an involvement of this pathway in AD pathogenesis, and support the hypothesis that it plays a functional role in AD development
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