Increased 5-lipoxygenase immunoreactivity in the hippocampus of patients with Alzheimer's disease.
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, beta-amyloid (Abeta) 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 Abeta 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 Abeta 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.
Ikonomovic
Milos D
MD
Department of Neurology, University of Pittsburgh School of Medicine, BSTWR S-521, Pittsburgh, PA 15261, USA. ikonomovicmd@upmc.edu
Abrahamson
Eric E
EE
Uz
Tolga
T
Manev
Hari
H
Dekosky
Steven T
ST
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D058225:Plaque, Amyloid / Q000201:enzymology
D016229:Amyloid beta-Peptides; D001094:Arachidonate 5-Lipoxygenase