Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington’s Disease

  • Scott Ayton
  • Peng Lei
  • Ambili T. Appukuttan
  • Thibault Renoir
  • Simote Foliaki
  • Feng Chen
  • Paul A. Adlard
  • Anthony J. Hannan
  • Ashley I. BushEmail author
Original Article


There is currently no disease-modifying treatment for Huntington’s disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.

Key Words

Huntington’s disease zinc cognition animal model 


Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Funding Information

This study was supported by funds from the Australian National Health & Medical Research Council (NHMRC: APP1113686). The Florey Institute of Neuroscience and Mental Health recognizes support from the Victorian Government, in particular funding from the Operational Infrastructure Support Grant. No funder of this study had any role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Compliance with Ethical Standards

All animal experiments were approved by the Howard Florey Animal Ethics Committee (permit # 13-110 and 14-056) and were conducted in accordance with state law and the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes as described by the National Health and Medical Research Council of Australia.


Dr. Bush is a shareholder in Prana Biotechnology Pty Ltd., Cogstate Pty Ltd., Eucalyptus Pty Ltd., Mesoblast Pty Ltd., Brighton Biotech LLC, Nextvet Ltd., Grunbiotics Pty Ltd., and Collaborative Medicinal Development LLC, and a paid consultant for Collaborative Medicinal Development. Dr. Adlard is a shareholder in, and consultant for, Prana Biotechnology Pty Ltd. The other authors declare that they have no competing interests.

Supplementary material

13311_2019_785_MOESM1_ESM.pdf (515 kb)
ESM 1 (PDF 514 kb)


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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Scott Ayton
    • 1
    • 2
    • 3
  • Peng Lei
    • 1
    • 2
    • 4
  • Ambili T. Appukuttan
    • 1
    • 2
  • Thibault Renoir
    • 2
  • Simote Foliaki
    • 1
    • 2
    • 3
  • Feng Chen
    • 1
    • 2
    • 3
  • Paul A. Adlard
    • 1
    • 2
    • 3
  • Anthony J. Hannan
    • 2
  • Ashley I. Bush
    • 1
    • 2
    • 3
    Email author
  1. 1.Melbourne Dementia Research CentreParkvilleAustralia
  2. 2.Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  3. 3.University of MelbourneParkvilleAustralia
  4. 4.Department of Neurology and State Key Laboratory of Biotherapy, West China HospitalSichuan University and Collaborative Center for BiotherapyChengduPeople’s Republic of China

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