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

Yasmina Manso, Gemma Comes, Juan C. López-Ramos, Mónica Belfiore, Amalia Molinero, Mercedes Giralt, Javier Carrasco, Paul A. Adlard, Ashley I. Bush, José María Delgado-García, Juan Hidalgo*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

© 2016 - IOS Press and the authors. All rights reserved. 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.
Original languageEnglish
Pages (from-to)81-95
JournalJournal of Alzheimer's Disease
Volume51
Issue number1
DOIs
Publication statusPublished - 27 Feb 2016

Keywords

  • Alzheimer' disease
  • amyloid plaques
  • behavior
  • body weight
  • gliosis
  • metallothionein-1
  • metals
  • survival
  • Tg2576

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