Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease
Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease
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DOI：
10.1016/j.expneurol.2012.02.012
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发表时间：
2012-05-01
影响因子：
5.3
通讯作者：
Bjorklund, A.
中科院分区：
文献类型：
--
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
帕金森病（PD）相关模型的开发对于更好地理解人类疾病的病理过程和评估有希望的治疗干预靶点是必不可少的。迄今为止，大多数临床前研究都是在成熟的啮齿动物和非人类灵长类动物模型中使用注射6-羟基多巴胺（6-OHDA）或1-甲基-4-苯基-1，2，3，6-四羟基吡啶（MPTP）进行的。使用腺相关病毒（AAV）载体过表达致病蛋白α-突触核蛋白（α-syn）提供了一种新的模型，其概括了人类疾病的许多特征。在本研究中，我们将AAV-α-syn大鼠模型与其中通过在纹状体（部分损伤）或内侧前脑束（完全损伤）中注射6-OHDA来损伤黑质-纹状体通路的模型进行了比较。随着时间的推移，行为变化的检查显示了不同的进展和运动障碍的程度。有趣的是，多巴胺（DA）神经元损失在毒素和AAV-alpha-syn模型中都是突出的。然而，观察到α-syn过表达的动物对于同等水平的运动异常表现出较少的细胞和末端损失。仅在alpha-syn大鼠模型中观察到显著和持续的轴突病理学。我们认为，虽然神经元和终端损失主要占在毒素为基础的模型中的行为障碍，类似的运动缺陷的结果从细胞死亡和功能障碍的组合，其余的黑质纹状体神经元的AAV-α-syn模型。虽然这两种模型已经被开发来模拟DA神经元缺陷，但它们在时间和神经病理学特征上不同，并且复制了人类疾病的病理生理学的不同方面。该研究表明，AAV-alpha-syn模型比其他两种6-OHDA损伤模型更接近地复制人类病理学。(C)2012 Elsevier Inc. All rights reserved.
Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein alpha-synuclein (alpha-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-alpha-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-alpha-syn models. However, alpha-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the alpha-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-alpha-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-alpha-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models. (C) 2012 Elsevier Inc. All rights reserved.