Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model.
BACKGROUND
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.


METHODS
In the present paper, we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of Tg2576 mice.


RESULTS
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.


CONCLUSIONS
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.
Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street MRB, 706A, Philadelphia, PA 19140, USA.
Jin
J
Chu
Domenico
D
Praticò
D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D058927:5-Lipoxygenase-Activating Proteins / Q000378:metabolism / Q000502:physiology*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D011897:Random Allocation
D058946:5-Lipoxygenase-Activating Protein Inhibitors; D058927:5-Lipoxygenase-Activating Proteins; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007211:Indoles; D011804:Quinolines; D012333:RNA, Messenger; C078266:MK 0591; D001094:Arachidonate 5-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases