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Increased 5-Lipoxygenase Immunoreactivity in the Hippocampus of Patients With Alzheimer's Disease

Milos D. Ikonomovic, Eric E. Abrahamson, Tolga Uz, Hari Manev and Steven T. DeKosky

Department of Neurology (MDI,EEA,STD) and Department of Psychiatry (MDI,STD), University of Pittsburgh, Pittsburgh, Pennsylvania, and Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois (TU,HM)

Correspondence to: Milos Ikonomovic, MD, Department of Neurology, University of Pittsburgh School of Medicine, BSTWR S-521, Pittsburgh, PA 15261. E-mail: ikonomovicmd{at}upmc.edu

The proinflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer's disease (AD), but its localization and association with the hallmark lesions of the disease, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), is unknown. This study examined the distribution and cellular localization of 5-LOX in the medial temporal lobe from AD and control subjects. The spatial relationship between 5-LOX immunoreactive structures and AD lesions was also examined. We report that, in AD subjects, 5-LOX immunoreactivity is elevated relative to controls, and its localization is dependent on the antibody-targeted portion of the 5-LOX amino acid sequence. Carboxy terminus–directed antibodies detected 5-LOX in glial cells and neurons, but less frequently in neurons with dystrophic (NFT) morphology. In contrast, immunoreactivity observed using 5-LOX amino terminus–directed antibodies was virtually absent in neurons and abundant in NFTs, neuritic plaques, and glia. Double-labeling studies showed a close association of 5-LOX–immunoreactive processes and glial cells with Aβ immunoreactive plaques and vasculature and also detected 5-LOX in tau immunoreactive and amyloid containing NFTs. Different immunolabeling patterns with antibodies against carboxy vs amino terminus of 5-LOX may be caused by post-translational modifications of 5-LOX protein in Aβ plaques and NFTs. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD. (J Histochem Cytochem 56:1065–1073, 2008)

Key Words: leukotrienes • inflammation • amyloid • neurodegeneration • hippocampus • dementia

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