title: Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Manso
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Comes
authors.affiliation: Division of Neurosciences, Universidad Pablo de Olavide, Sevilla, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: López-Ramos
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Belfiore
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Molinero
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Giralt
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.affiliation: The Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.affiliation: The Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Division of Neurosciences, Universidad Pablo de Olavide, Sevilla, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Delgado-García
authors.affiliation: Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain.|Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000209:etiology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D053513:Matrix Metalloproteinase 16 / Q000235:genetics / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011596:Psychomotor Disorders / Q000209:etiology / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; C530099:MT1A protein, human; D008668:Metallothionein; D053513:Matrix Metalloproteinase 16
keywords: Alzheimer’ disease; Tg2576; amyloid plaques; behavior; body weight; gliosis; metallothionein-1; metals; survival