Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model.
Neurodegeneration-Like Pathological and Behavioral Changes in an AAV9-Mediated p25 Overexpression Mouse Model.
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DOI：
10.3233/jad-160191
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Xiao Zhou;Jianou Huang;Suyue Pan;Miaojing Xu;R. He;Z. Ji;Yafang Hu
中科院分区：
文献类型：
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作者：
Xiao Zhou;Jianou Huang;Suyue Pan;Miaojing Xu;R. He;Z. Ji;Yafang Hu
背景高表达人p25的转基因小鼠模型对p25在神经退行性疾病中的体内神经毒性机制有重要作用。然而，操纵现有的转基因小鼠模型是耗时的。目的建立重组腺相关病毒血清9型(RAAV9)高表达p25诱导的小鼠神经退行性变模型。方法小鼠尾静脉注射突触素启动子驱动的编码GFP融合p25的AAV9-GFP-p25和对照AAV9-GFP。对p25的表达、神经退行性病变和行为改变进行评估。结果注射病毒后1周，活体成像即可检测到GFP的表达。值得注意的是，在AAV9-GFP-p25小鼠的大脑皮质、海马体和小脑中明显发现了p25的广泛表达。此外，注射AAV9-GFP-p25小鼠约一个月后，通过7T MRI检查发现其海马区体积缩小。此外，这些AAV9-GFP-p25小鼠在注射病毒后3个月到6个月表现出进行性记忆障碍。最后，在病毒感染后6个月左右，这些p25小鼠体内过度磷酸化的tau蛋白、神经原纤维缠结、激活的星形胶质细胞和小胶质细胞数量增加。然而，AAV9介导的p25过表达并没有显著地诱导海马区和皮质中的淀粉样蛋白β斑块、明显的神经元丢失和细胞凋亡。结论AAV9介导的p25过表达小鼠模型是一种实用的神经退行性变样病理和行为改变模型，为体内p25功能的研究提供了一种简便、省时的方法，也为开发抗p25神经毒性药物提供了一种新的工具。
BACKGROUND The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. OBJECTIVE Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). METHODS AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. RESULTS GFP expression was detected by in vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. CONCLUSION The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo, as well as an alternative tool for development of drugs against neurotoxic of p25.