Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
Neurobiol Dis. 2021 Jul;154:105339. doi: 10.1016/j.nbd.2021.105339. Epub 2021 Mar 26.
Moyamoya-like vasculopathy, the "puff of smoke"-like small vessels in the brain, is initially identified in patients with Moyamoya disease (MMD), a rare cerebrovascular disease, and later found in patients with various types of neurological conditions, including Down syndrome, Stroke, and vascular dementia. It is thus of interest to understand how this vasculopathy is developed. Here, we provided evidence for cortical astrocytic neogenin (NEO1) deficiency to be a risk factor for its development. NEO1, a member of deleted in colorectal cancer (DCC) family netrin receptors, was reduced in brain samples of patients with MMD. Astrocytic Neo1-loss resulted in an increase of small blood vessels (BVs) selectively in the cortex. These BVs were dysfunctional, with leaky blood-brain barrier (BBB), thin arteries, and accelerated hyperplasia in veins and capillaries, resembled to the features of moyamoya-like vasculopathy. Additionally, we found that both MMD patient and Neo1 mutant mice exhibited altered gene expression in their cortex in proteins critical for not only angiogenesis [e.g., an increase in vascular endothelial growth factor (VEGFa)], but also axon guidance (e.g., netrin family proteins) and inflammation. In aggregates, these results suggest a critical role of astrocytic NEO1-loss in the development of Moyamoya-like vasculopathy, providing a mouse model for investigating mechanisms of Moyamoya-like vasculopathy.
烟雾病样血管病，即脑内“烟雾状”小血管，最初在烟雾病（MMD）患者中被发现，MMD 是一种罕见的脑血管疾病，后来在各种类型的神经疾病患者中发现，包括唐氏综合征、中风和血管性痴呆。因此，了解这种血管病是如何发展的很有意义。在这里，我们提供的证据表明皮质星形胶质细胞神经调节蛋白 1（NEO1）缺乏是其发展的一个风险因素。NEO1 是Deleted in colorectal cancer（DCC）家族轴突导向因子 netrin 受体的一员，在 MMD 患者的脑样本中减少。星形胶质细胞 NEO1 缺失导致小血管（BVs）选择性增加，特别是在皮质。这些 BVs 功能失调，血脑屏障（BBB）渗漏，动脉变薄，静脉和毛细血管增生加速，类似于烟雾病样血管病的特征。此外，我们发现 MMD 患者和 Neo1 突变小鼠的皮质中都有改变的基因表达，这些基因不仅对血管生成（如血管内皮生长因子 A（VEGFa）增加），而且对轴突导向（如 netrin 家族蛋白）和炎症都很重要。总的来说，这些结果表明星形胶质细胞 NEO1 缺失在烟雾病样血管病的发展中起着关键作用，为研究烟雾病样血管病的机制提供了一个小鼠模型。
