title: Metallo-complex activation of neuroprotective signalling pathways as a therapeutic treatment for Alzheimer's disease.
abstract: Alzheimer's disease is the most common neurodegenerative disease of the elderly and although some drugs may delay cognitive impairment, an effective treatment has not yet been found. Extracellular deposition of amyloid-beta (Abeta) plaques, intracellular hyperphosphorylation of the microtubule associated protein, tau and elevated oxidative stress have long been a focus for neurotherapeutic strategies. More recently biometal interactions with Abeta have become a feasible target as they appear to play a significant role in the pathogenesis of this devastating disease. Metal ligands such as 8-hydroxyquinoline derivatives have been developed that alter these interactions and promote clearance of amyloid deposits. A novel neurotherapeutic approach may involve activation of neuronal cell signalling mechanisms using metallo-complexes. Copper or zinc complexes can activate phosphoinositol-3-kinase leading to downstream modulation of glycogen synthase kinase-3 and extracellular signal regulated kinase and this results in decreased tau and Abeta levels. These approaches may offer a new strategy for treating AD. Further in vivo investigation is required to elucidate the mechanism of action of these metallo-complexes in vivo and determine their efficacy and safety as potential treatments of neurodegenerative diseases.
authors.affiliation: Department of Pathology, The University of Melbourne, 3010, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Bica
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008670:Metals / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D015125:Oxyquinoline / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D015032:Zinc / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D008670:Metals; D018696:Neuroprotective Agents; D016875:tau Proteins; D015125:Oxyquinoline; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D015032:Zinc