Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Manso, Yasmina^{a; b; 1; 2} | Comes, Gemma^{a; b; 1} | López-Ramos, Juan C.^c | Belfiore, Mónica^{a; b} | Molinero, Amalia^{a; b} | Giralt, Mercedes^{a; b} | Carrasco, Javier^{a; b} | Adlard, Paul A.^d | Bush, Ashley I.^d | Delgado-García, José María^c | Hidalgo, Juan^{a; b; *}

Affiliations: [a] Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences Bellaterra, Barcelona, Spain | [b] Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain | [c] Division of Neurosciences, Universidad Pablo de Olavide, Sevilla, Spain | [d] The Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria, Australia

Correspondence: [*] Correspondence to: Juan Hidalgo, PhD, Unidad de Fisiología Animal, Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Biociencias, Edificio C, Universidad Autónoma de Barcelona, Bellaterra, Barcelona 08193, Spain. Tel.: +34 935812037; Fax: +34 935812390; E-mail: juan.hidalgo@uab.cat.

Note: [1] These authors contributed equally to this work.

Note: [2] Present address: Developmental Neurobiology and Regeneration Lab, Lab A1B1, Parc Científic de Barcelona, Barcelona, Spain.

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.

Keywords: Alzheimer’ disease, amyloid plaques, behavior, body weight, gliosis, metallothionein-1, metals, survival, Tg2576

DOI: 10.3233/JAD-151025

Journal: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 81-95, 2016