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(American Journal of Pathology. 2004;164:1655-1662.)
© 2004 American Society for Investigative Pathology

12/15-Lipoxygenase Is Increased in Alzheimer’s Disease

Possible Involvement in Brain Oxidative Stress

Domenico Praticò^*, Victoria Zhukareva, Yuemang Yao^*, Kunihiro Uryu, Colin D. Funk^*, John A. Lawson^*, John Q. Trojanowski and Virginia M.-Y. Lee

From the Centers for Experimental Therapeutics^* and Neurodegenerative Disease Research, and the Departments of Pharmacology, Pathology, and Laboratory Medicine, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that oxidative stress could play a functional role in its pathogenesis. Lipoxygenase (LOX) enzymes by oxidizing polyunsaturated fatty acids synthesize hydroperoxyacids, which are potent pro-oxidant mediators. Because circumstantial evidence suggests that 12/15-LOX is a major source of oxidative stress, we investigated the protein levels and activity of this enzyme in different brain regions of histopathologically confirmed AD and control cases. Using quantitative Western blot analysis we demonstrated that in affected frontal and temporal regions of AD brains the amount of 12/15-LOX was higher compared with controls, whereas no difference between the two groups was detected in the cerebellum. This observation was confirmed by immunohistochemical studies. Levels of 12/15-hydroxyeicosatetraenoic acids, metabolic products of 12/15-LOX, were also markedly elevated in AD brains compared to controls. This increase directly correlated with brain lipid peroxidation, and inversely with vitamin E levels. Finally, genetic deletion of this enzyme in vitro resulted in a reduction of the cellular oxidative stress response after incubation with H₂O₂ or amyloid ß. These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder.

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