A novel rhesus macaque model of Huntington's disease recapitulates key neuropathological changes along with motor and cognitive decline.
Alison R WeissWilliam A LiguoreKristin BrandonXiaojie WangZheng LiuJacqueline S DomireDana ButtonSathya SrinivasanChristopher D KroenkeJodi L McBridePublished in: eLife (2022)
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.
Keyphrases
- working memory
- cognitive decline
- white matter
- endothelial cells
- gene therapy
- resting state
- high resolution
- end stage renal disease
- newly diagnosed
- mild cognitive impairment
- multiple sclerosis
- minimally invasive
- sars cov
- poor prognosis
- chronic kidney disease
- induced pluripotent stem cells
- ejection fraction
- functional connectivity
- attention deficit hyperactivity disorder
- pluripotent stem cells
- cerebral ischemia
- high throughput
- transcranial direct current stimulation
- peritoneal dialysis
- wild type
- gene expression
- prognostic factors
- patient reported outcomes
- blood brain barrier
- dna methylation
- single cell
- copy number
- long non coding rna
- coronary artery disease
- fluorescence imaging