Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer’s disease mouse model
Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street MRB, 706A, Philadelphia, PA, 19140, USA
Journal of Neuroinflammation 2012, 9:127 doi:10.1186/1742-2094-9-127Published: 14 June 2012
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. 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.
In the present paper, we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of Tg2576 mice.
Amyloid 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.
These 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.