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

Milos D. Ikonomovic ^1*, Eric E. Abrahamson ¹, Tolga Uz ¹, Hari Manev ¹ and Steven T. DeKosky ¹

¹ Departments of Neurology (MDI,EEA,STD) and Psychiatry (MDI,STD), University of Pittsburgh, Pittsburgh, Pennsylvania, and Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois (TU,HM)

^* To whom correspondence should be addressed. E-mail: ikonomovicmd{at}upmc.edu.

Submitted on May 14, 2008
Accepted on 21 July 2008

	Abstract

The pro-inflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer’s disease (AD), but its localization and association with the hallmark lesions of the disease, -amyloid (A) plaques and neurofibrillary tangles (NFT), is unknown. The present 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 NFT, neuritic plaques and glia. Double-labeling studies revealed a close association of 5-LOX-immunoreactive processes and glial cells with A immunoreactive plaques and vasculature, and also detected 5-LOX in tau immunoreactive and amyloid containing NFT. Different immunolabeling patterns with antibodies against carboxy- versus amino-terminus of 5-LOX may be due to post-translational modifications of 5-LOX protein in A plaques and NFT. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD.

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

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