Abstract
ABSTRACTRecently developed therapeutic approaches for the treatment of Huntington's disease (HD) require preclinical testing in large animal models. The minipig is a suitable experimental animal because of its large gyrencephalic brain, body weight of 70-100 kg, long lifespan, and anatomical, physiological and metabolic resemblance to humans. The Libechov transgenic minipig model for HD (TgHD) has proven useful for proof of concept of developing new therapies. However, to evaluate the efficacy of different therapies on disease progression, a broader phenotypic characterization of the TgHD minipig is needed. In this study, we analyzed the brain tissues of TgHD minipigs at the age of 48 and 60-70 months, and compared them to wild-type animals. We were able to demonstrate not only an accumulation of different forms of mutant huntingtin (mHTT) in TgHD brain, but also pathological changes associated with cellular damage caused by mHTT. At 48 months, we detected pathological changes that included the demyelination of brain white matter, loss of function of striatal neurons in the putamen and activation of microglia. At 60-70 months, we found a clear marker of neurodegeneration: significant cell loss detected in the caudate nucleus, putamen and cortex. This was accompanied by clusters of structures accumulating in the neurites of some neurons, a sign of their degeneration that is also seen in Alzheimer's disease, and a significant activation of astrocytes. In summary, our data demonstrate age-dependent neuropathology with later onset of neurodegeneration in TgHD minipigs.
Highlights
Huntington’s disease (HD) is an inherited progressive neurodegenerative disease without a current effective treatment
Because motor and cognitive phenotype is connected with weight loss, we measured the animal body mass index (ABMI), a weight correlated by height and length of the animal
While just a slight non-significant decrease was revealed in the ABMI of transgenic minipig model for HD (TgHD) compared to WT boars at 6-7 years, a significant decrease was measured in 6- to 7-year-old TgHD sows (6 years: P=0.0286; 7 years: P=0.0357; 6-7 years: P=0.0002) in comparison to the WT controls
Summary
Huntington’s disease (HD) is an inherited progressive neurodegenerative disease without a current effective treatment. It is caused by CAG triplet expansion in exon 1 of the huntingtin gene (HTT), which gives rise to mutant huntingtin protein (mHTT). HD manifests typically between 30 and 50 years of age Soluble mHTT monomers, N-terminal fragments and mHTT oligomers, so-called mHTT intermediates of the aggregation pathway, were described as a trigger of cellular dysfunction in the affected tissues (Hoffner et al, 2007; Lajoie and Snapp, 2010)
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