Metallo-complex activation of neuroprotective signalling pathways as a therapeutic treatment for Alzheimer's disease.
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.
Bica
Laura
L
Department of Pathology, The University of Melbourne, 3010, Victoria, Australia.
Crouch
Peter J
PJ
Cappai
Roberto
R
White
Anthony R
AR
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
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