title: Effects of a tacrine-8-hydroxyquinoline hybrid (IQM-622) on Aβ accumulation and cell death: involvement in hippocampal neuronal loss in Alzheimer's disease.
abstract: Several studies have implicated the enzyme acetylcholinesterase (AChE) as well as several biometals in the pathogenesis of Alzheimer's disease (AD). A multifunctional molecule, the hybrid tacrine-8-hydroxyquinoline (named IQM-622), displays cholinergic, antioxidant, copper-complexing and neuroprotective properties. Using in vitro and in vivo models, we investigated the modulating effects of IQM-622 on amyloid β-protein (Aβ)-induced pathology as well as on chemically induced neurodegeneration by domoic acid. In the first experimental model, we observed a significant decrease in brain Aβ deposits in IQM-622-treated APP/Ps1 mice for four weeks. Moreover, IQM-622 promoted the degradation of intracellular Aβ in astrocytes, and protected against Aβ toxicity in cultured astrocytes and neurons. These findings suggest that the neuroprotective effect of IQM-622 is not only related to AChE inhibition, but also involves other mechanisms, including the modulation of Aβ-degradation pathways in AD brain. In this study we also compare the neuronal loss in CA1 hippocampal field of AD patients and of mice treated with domoic acid, giving similar patterns. Thus, we used a second experimental model by killing hippocampal neurons by domoic acid damage, in which IQM-622 increased survival in the CA1 and dentate gyrus regions of the hippocampus. Our observations suggest that administration of IQM-622 may have significant beneficial effects in neurodegenerative diseases, including AD, which course with acute or progressive neuronal death.
authors.affiliation: Neuroscience Group, Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain.
authors.forename: Desiree
authors.initials: D
authors.lastname: Antequera
authors.forename: Marta
authors.initials: M
authors.lastname: Bolos
authors.forename: Carlos
authors.initials: C
authors.lastname: Spuch
authors.forename: Consuelo
authors.initials: C
authors.lastname: Pascual
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Fernandez-Bachiller
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006912:Hydroxyquinolines; D018696:Neuroprotective Agents; D053764:Presenilin-1; C574896:tacrine-8-hydroxyquinoline; D013619:Tacrine