A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with motor and cognitive decline

Alison R. Weiss, William A. Liguore, Kristin Brandon, Xiaojie Wang, Zheng Liu, Jacqueline S. Domire, Dana Button, Sathya Srinivasan, Christopher D. Kroenke, Jodi McBride

Research output: Contribution to journalArticlepeer-review

Abstract

We created a new nonhuman primate model of the genetic neurodegenerative disorder Huntington's disease (HD) by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and AAV2.retro, each expressing a fragment of human mutant HTT (mHTT) into the caudate and putamen of adult rhesus macaques. This modeling strategy results in expression of mutant huntingtin protein (mHTT) and aggregate formation in the injected brain regions, as well as dozens of other cortical and subcortical brain regions affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 30 months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed working memory decline and progressive motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. Taken together, we have developed a novel macaque model of HD that may be used to develop disease biomarkers and screen promising therapeutics.

Original languageEnglish (US)
JournaleLife
Volume11
DOIs
StatePublished - Oct 7 2022

Keywords

  • adeno-associated virus
  • animal model
  • cognitive behavior
  • huntington's disease
  • motor behavior
  • neuroimaging
  • neuroscience
  • rhesus macaque

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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