High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease.
High-fat diet-induced diabetes leads to vascular alterations, pericyte reduction, and perivascular depletion of microglia in a 6-OHDA toxin model of Parkinson disease.
复制标题
在帕金森病的6-OHDA毒素模型中，高脂饮食诱导的糖尿病导致血管改变、周细胞减少和血管周围小胶质细胞枯竭。
DOI：
10.1186/s12974-021-02218-8
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发表时间：
2021-08-10
影响因子：
9.3
通讯作者：
Paul G
中科院分区：
文献类型：
--
作者：
Elabi OF;Cunha JPMCM;Gaceb A;Fex M;Paul G
糖尿病已被认为是导致帕金森病（PD）发生和进展的危险因素。虽然有几种假说提出了一些不同的机制，糖尿病引起的PD的恶化，很少有人注意到糖尿病和PD共享病理微血管改变的大脑。目前尚不清楚糖尿病与PD在血管界面的相互作用特征。我们将2型糖尿病（DMT 2）的高脂饮食（HFD）模型与雄性小鼠PD的6-OHDA损伤模型相结合。我们分析了胰岛素抵抗和多巴胺能黑质纹状体病理学程度之间的关系。我们进一步评估了两种病理学的相互作用对运动缺陷的影响，使用一组行为测试和小胶质细胞活化，使用免疫组织化学。通过分析血管密度和分支点、周细胞密度、血脑屏障渗漏以及纹状体中微血管和小胶质细胞之间的相互作用，在组织学上研究血管病理学。获得不同程度的PD损伤，导致中度和重度多巴胺能细胞损失。即使HFD范例没有影响黑质纹状体病变的程度，在急性毒素诱导的PD模型中使用，我们观察到的运动表现的帕金森病小鼠的饮食的部分恶化。重要的是，中度PD病理学和HFD的组合导致显著的周细胞耗竭，不存在血管生成反应，以及小胶质细胞/血管相互作用的显著减少，表明血管病理学恶化。这项研究提供了DMT 2和PD在脑微血管系统中相互作用的第一个证据，涉及小胶质细胞与微血管相互作用的变化。这些病理变化可能有助于PD与糖尿病相关时加速进展的病理机制。在线版本包含补充材料，可通过10.1186/s12974-021-02218-8获得。
Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson’s disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known. We combined a high-fat diet (HFD) model of diabetes mellitus type 2 (DMT2) with the 6-OHDA lesion model of PD in male mice. We analyzed the association between insulin resistance and the achieved degree of dopaminergic nigrostriatal pathology. We further assessed the impact of the interaction of the two pathologies on motor deficits using a battery of behavioral tests and on microglial activation using immunohistochemistry. Vascular pathology was investigated histologically by analyzing vessel density and branching points, pericyte density, blood–brain barrier leakage, and the interaction between microvessels and microglia in the striatum. Different degrees of PD lesion were obtained resulting in moderate and severe dopaminergic cell loss. Even though the HFD paradigm did not affect the degree of nigrostriatal lesion in the acute toxin-induced PD model used, we observed a partial aggravation of the motor performance of parkinsonian mice by the diet. Importantly, the combination of a moderate PD pathology and HFD resulted in a significant pericyte depletion, an absence of an angiogenic response, and a significant reduction in microglia/vascular interaction pointing to an aggravation of vascular pathology. This study provides the first evidence for an interaction of DMT2 and PD at the brain microvasculature involving changes in the interaction of microglia with microvessels. These pathological changes may contribute to the pathological mechanisms underlying the accelerated progression of PD when associated with diabetes. The online version contains supplementary material available at 10.1186/s12974-021-02218-8.
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