Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.
Mutant G2019S-LRRK2 Induces Abnormalities in Arteriolar Cerebral Blood Volume in Mouse Brains: An MRI Study.
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DOI：
10.1159/000510387
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hua J
中科院分区：
文献类型：
--
作者：
Ning B;Guo G;Gu C;Xu J;Bibic A;He X;Liu H;Chen L;Wei Z;Duan W;Liu P;Lu H;van Zijl PCM;Ross CA;Smith W;Hua J
帕金森病（PD）是第二常见的神经退行性疾病，也是最常见的运动障碍，其特征在于由中脑多巴胺（DA）神经元损失引起的运动障碍。软脑膜小动脉和小动脉是脑组织中营养物质和氧气局部输送的主要途径，已在许多神经退行性疾病（包括PD）中报告了其异常。LRRK 2突变导致遗传性PD并导致散发性PD。最常见的PD连锁突变LRRK 2 G2019 S占白人人群中PD遗传形式的20-47%。人LRRK 2 G2019 S转基因小鼠模型显示PD样运动障碍，并用于鉴定新型LRRK 2抑制剂，其为研究PD中的微血管异常提供了有用的模型。在LRRK 2小鼠PD模型中，使用基于流入的血管空间占用（iVASO）MRI技术研究不同脑区的小动脉脑血容量（CBVa）异常。在9月龄的5只雌性和7只雄性非转基因（nTg）、3只雌性和4只雄性野生型（WT）-LRRK 2以及5只雌性和7只雄性G2019 S-LRRK 2小鼠中进行解剖和iVASO MRI扫描。计算并比较黑质、嗅皮层和前额叶皮层的CBVa。与nTg小鼠相比，G2019 S-LRRK 2小鼠在SN中显示出CBVa降低，但在雄性和雌性组中的嗅觉和前额皮质中的CBVa增加，而WT-LRRK 2小鼠在SN（雄性和雌性）、嗅觉（雌性）和前额（雌性）皮质中的CBVa没有变化，但仅在雄性组中的嗅觉和前额皮质中的CBVa轻微增加。在PD的G2019 S-LRRK 2小鼠模型中检测小动脉和小动脉（CBVa）的血容量的改变。SN和皮质中CBVa的相反变化表明PD病理学可能在不同的脑区域中具有不同的影响。我们的研究结果表明CBVa作为临床PD研究的标志物的潜在价值。
Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine (DA) neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20–47% of genetic forms of PD in Caucasian population. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space-occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. Anatomic and iVASO MRI scans were performed in 5 female and 7 male non-transgenic (nTg), 3 female and 4 male wild type (WT)-LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9-month age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex and prefrontal cortex. Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female) and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.
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