Transgenic minipig model of Huntington's disease exhibiting gradually progressing neurodegeneration

Abstract

Recently developed therapeutic approaches for the treatment of Huntington's disease (HD) require pre-clinical testing in large animal models. 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 been proven useful for proof of concept of developing new therapies. However, to evaluate the efficacy of different therapies on the disease progression a broader phenotypic characterization of the TgHD minipig is needed. In this study, we analysed the brain tissues of TgHD minipigs at the age of 48 and 60-70 months and compared them to wild type (WT) 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 including 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, a 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 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 the TgHD minipigs.