prostaglandin-h2 and Alzheimer-Disease

Many studies have shown that chronic inflammation occurs in the brain of patients with Alzheimer's disease (AD). It is well known that long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate the cognitive decline of AD patient and elderly. Several inflammatory cytokines produced in the metabolism of arachidonic acid (AA) are closely related to inflammatory diseases. Lipoxygenases (LOXs) and cyclooxygenases (COXs) play a crucial role in the AA network, the products eicosanoids have an important impact on the progression of AD. Although there are many arguments and conflicting evidence, currently LOXs and COXs are still the hot topics in the research on AD pathogenesis and drug development. Here, we review the progress in research on COXs and LOXs, including their actions on CNS and their association with AD, and explore the feasibility of LOXs and COXs as targets for the drugs to prevent and/or treat AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Brain; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Lipoxygenase Inhibitors; Lipoxygenases; Prostaglandin H2; Prostaglandin-Endoperoxide Synthases

The formation of cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive gamma-ketoaldehydes, levuglandin (LG) E(2) and LGD(2). These gamma-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Case-Control Studies; Hippocampus; Humans; Lactams; Lysine; Nerve Tissue Proteins; Prostaglandin H2; Prostaglandins E; Severity of Illness Index

Epidemiologic evidence implicates cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid beta peptide. The product of the oxygenation of arachidonic acid by the cyclooxygenases, prostaglandin H2 (PGH2), rearranges non-enzymatically to several prostaglandins, including the highly reactive gamma-keto aldehydes, levuglandins E2 and D2. We demonstrate that PGH2 markedly accelerates the formation of dimers and higher oligomers of amyloid beta1-42. This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking cyclooxygenase activity to the formation of oligomers of amyloid beta.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Chelating Agents; Dimerization; Edetic Acid; Electrophoresis, Polyacrylamide Gel; Macromolecular Substances; Microscopy, Electron; Peptide Fragments; Polymers; Prostaglandin H2; Prostaglandins E; Prostaglandins H; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization