Mantovani Susanna, Gordon Richard, Li Rui, Christie Daniel C, Kumar Vinod, Woodruff Trent M
School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia and Wesley Medical Research, Auchenflower, Brisbane, QLD, Australia.
School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia and.
Hum Mol Genet. 2016 May 1;25(9):1780-91. doi: 10.1093/hmg/ddw050. Epub 2016 Feb 21.
Huntington's disease (HD) is an incurable neurodegenerative condition characterized by progressive motor and cognitive dysfunction, and depletion of neurons in the striatum. Recently, BACHD transgenic mice expressing the full-length human huntingtin gene have been generated, which recapitulate some of the motor and cognitive deficits seen in HD. In this study, we carried out a series of extensive behavioural and neuropathological tests on BACHD mice, to validate this mouse for preclinical research. Transgenic C57BL/6J BACHD and litter-matched wild-type mice were examined in a battery of motor and cognitive function tests at regular intervals up to 12 months of age. Brains from these mice were also analysed for signs of neurodegeneration and striatal and cortical volume sizes compared using anatomic 16.4T magnetic resonance imaging (MRI) brain scans. BACHD mice showed progressive motor impairments on rotarod and balance beam tests starting from 3 months of age, were hypoactive in the open field tests starting from 6 months of age, however, showed no alterations in gait and grip strength at any age. Surprisingly, despite these distinct motor deficits, no signs of neuronal loss, gliosis or blood-brain barrier degeneration were observed in the striatum of 12-month-old mice. MRI brain scans confirmed no reduction in striatal or cortical volumes at 12 months of age, and BACHD mice had a normal lifespan. These results demonstrate that classical Huntington's-like motor impairments seen in this transgenic model, do not occur due to degeneration of the striatum, and thus caution against the use of this model for preclinical studies into HD.
亨廷顿舞蹈症（HD）是一种无法治愈的神经退行性疾病，其特征为进行性运动和认知功能障碍，以及纹状体中的神经元缺失。最近，已培育出表达全长人类亨廷顿基因的BACHD转基因小鼠，该小鼠重现了HD中出现的一些运动和认知缺陷。在本研究中，我们对BACHD小鼠进行了一系列广泛的行为和神经病理学测试，以验证该小鼠用于临床前研究的有效性。对转基因C57BL/6J BACHD小鼠和同窝匹配的野生型小鼠在长达12个月龄时定期进行一系列运动和认知功能测试。还对这些小鼠的大脑进行分析，以寻找神经退行性变的迹象，并使用解剖学16.4T磁共振成像（MRI）脑部扫描比较纹状体和皮质的体积大小。BACHD小鼠从3个月龄开始在转棒试验和平衡木试验中表现出进行性运动障碍，从6个月龄开始在旷场试验中活动减少，然而，在任何年龄时其步态和握力均无改变。令人惊讶的是，尽管存在这些明显的运动缺陷，但在12个月龄小鼠的纹状体中未观察到神经元丢失、胶质细胞增生或血脑屏障退化的迹象。MRI脑部扫描证实12个月龄时纹状体或皮质体积没有减小，且BACHD小鼠寿命正常。这些结果表明，在该转基因模型中看到的典型亨廷顿样运动障碍并非由于纹状体退化所致，因此在将该模型用于HD的临床前研究时需谨慎。
