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5-Lipoxygenase gene disruption reduces amyloid-β pathology in a mouse model of Alzheimer’s disease

Omidreza Firuzi^*, Jiamin Zhuo^*, Cinzia M. Chinnici^*, Thomas Wisniewski and Domenico Praticò^*,1

^* Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and

New York University School of Medicine, Department of Neurology, Psychiatry and Pathology, New York, New York, USA

¹Correspondence: Dept. of Pharmacology, Temple University, 3420 North Broad St., Medical Research Bldg., Room 706A, Philadelphia, PA 19140, USA. E-mail: praticod{at}temple.edu

5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer’s disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-β (Aβ) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64–80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Aβ levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-β precursor protein (APP) levels and processing, or Aβ catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, Aβ formation, secondary to correspondent changes in -secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating -secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD.—Firuzi, O., Zhuo, J., Chinnici, C. M., Wisniewski, T., Praticò, D. 5-Lipoxygenase gene disruption reduces amyloid-β pathology in a mouse model of Alzheimer’s disease.

Key Words: -secretase • Tg2576 • Aβ • amyloid-β precursor protein • leukotrienes

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