title: Copper chelator induced efficient episodic memory recovery in a non-transgenic Alzheimer's mouse model.
abstract: Alzheimer's disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aβ amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aβ(1-42) peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aβ(42-1) peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.
authors.affiliation: Université de Toulouse, UPS, Centre de Recherches sur la Cognition Animale, Toulouse, France.
authors.forename: Johnatan
authors.initials: J
authors.lastname: Ceccom
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coslédan
authors.forename: Hélène
authors.initials: H
authors.lastname: Halley
authors.forename: Bernard
authors.initials: B
authors.lastname: Francès
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Lassalle
authors.forename: Bernard
authors.initials: B
authors.lastname: Meunier
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000503:physiopathology*; D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002614:Chelating Agents / Q000009:adverse effects / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D003300:Copper / Q000737:chemistry*; D004195:Disease Models, Animal; D007267:Injections; D008297:Male; D061212:Memory, Episodic; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; C080436:8-aminoquinoline