The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain
The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain
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DOI：
10.1016/j.expneurol.2011.11.031
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Poirier, J.
中科院分区：
文献类型：
--
作者：
Domenger, D.;Dea, D.;Poirier, J.
载脂蛋白 E (apoE) 被认为是大脑重塑的关键因素。它已被证明在外周和中枢损伤后会增加，调节阿尔茨海默病 (AD) 等神经退行性疾病的修复能力，并与许多其他神经退行性疾病相关。据推测，apoE 的这种特殊功能是与 AD 发病风险和年龄密切相关的基础。 ApoE 与帕金森病 (PD) 的关联研究产生了矛盾的结果，帕金森病是第二常见的神经退行性疾病，但与帕金森病发病年龄和痴呆症的关联却很突出。我们在此研究 apoE 是否参与对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的变性的反应，该变性模拟小鼠纹状体的 PD 样传入神经阻滞，并参与代偿性神经支配机制。我们检测了退行性和反应性再生期间不同大脑结构中apoE及其关键受体、低密度脂蛋白受体（LDLR）和LDLR相关蛋白（LRP）以及反应性星形胶质细胞标记物胶质纤维酸性蛋白（GFAP）的基因表达和蛋白水平的变化。在纹状体中，治疗后 1 天 GFAP、apoE 和 LRP mRNA 的上调与多巴胺 (DA) 水平的显着降低、酪氨酸羟化酶蛋白含量的损失以及多巴胺能代谢的代偿性增加相关。随后恢复到接近控制水平与纹状体重新神经支配的迹象相一致：所有这些都与 apoE 在退化过程和再生期间的作用一致。我们还发现，这种级联在海马体中被激活，并且比纹状体中更活跃，其中 LDLR 表达有特殊贡献。海马的激活与神经化学物质的大量减少无关，但似乎反映了 DA 代谢的局部微妙变化以及该结构中可塑性相关事件的调节。这项研究提供了 PD 小鼠模型中 apoE/apoE 受体级联激活的第一个证据，特别是在 MPTP 诱导的纹状体传入神经阻滞中。结果也与 apoE 在大脑修复中的假设作用非常一致，但提出了基因表达可能发生病变和区域特异性改变的问题。 (C) 2011 年，爱思唯尔公司出版。
Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1 day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression. (C) 2011 Published by Elsevier Inc.