Glial Vascular Degeneration in CADASIL
Glial Vascular Degeneration in CADASIL
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DOI：
10.3233/jad-2010-100036
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
de la Monte, Suzanne M.
中科院分区：
文献类型：
--
作者：
Brennan-Krohn, Thea;Salloway, Stephen;de la Monte, Suzanne M.
CADASIL是一种遗传性血管性痴呆，由19号染色体Notch 3基因突变引起。然而，对血管变性的机制知之甚少。我们通过测量3个CADASIL和6个对照组大脑皮质和白质中胰岛素、IGF-1和IGF-2受体、Notch 1、Notch 3和天冬氨酸-(天门冬氨酰基)-β-羟基酶(AAH)的表达，表征了可能在CADASIL中被破坏的Notch信号通路的上游成分。我们通过测量神经元、少突胶质细胞和星形胶质细胞相应的mRNA，以及通过测量分离血管中平滑肌肌动蛋白(SMA)和内皮素-1的表达来评估血管变性指数，以评估CADASIL相关的细胞损失。免疫组织化学染色检测SMA变性程度。CADASIL组大鼠脑白质Notch 1、Notch 3、AAH、SMA、IGF受体、髓鞘相关糖蛋白和胶质纤维酸性蛋白表达水平降低，SMA、IGF受体、Notch 1和Notch 3血管表达减少。此外，我们发现CADASIL相关的SMA减少，以及白质和脑膜血管中泛素免疫反应性的增加。CADASIL大脑皮层未见基因表达或免疫反应异常。总之，CADASIL的分子异常主要局限于白质和白质血管，与神经病理损害的分布相对应。这些初步结果表明，CADASIL是由神经胶质细胞和血管退行性变介导的，IGF受体和AAH的表达减少，AAH调节Notch的表达和功能。
CADASIL is a genetic vascular dementia caused by mutations in the Notch 3 gene on Chromosome 19. However, little is known about the mechanisms of vascular degeneration. We characterized upstream components of Notch signaling pathways that may be disrupted in CADASIL, by measuring expression of insulin, IGF-1, and IGF-2 receptors, Notch 1, Notch 3, and aspartyl-(asparaginyl)-beta-hydroxylase (AAH) in cortex and white matter from 3 CADASIL and 6 control brains. We assessed CADASIL-associated cell loss by measuring mRNA corresponding to neurons, oligodendroglia, and astrocytes, and indices of vascular degeneration by measuring smooth muscle actin (SMA) and endothelin-1 expression in isolated vessels. Immunohistochemical staining was used to assess SMA degeneration. Significant abnormalities, including reduced cerebral white matter mRNA levels of Notch 1, Notch 3, AAH, SMA, IGF receptors, myelin-associated glycoproteins, and glial fibrillary acidic protein, and reduced vascular expression of SMA, IGF receptors, Notch 1, and Notch 3 were detected in CADASIL-lesioned brains. In addition, we found CADASIL-associated reductions in SMA, and increases in ubiquitin immunoreactivity in the media of white matter and meningeal vessels. No abnormalities in gene expression or immunoreactivity were observed in CADASIL cerebral cortex. In conclusion, molecular abnormalities in CADASIL are largely restricted to white matter and white matter vessels, corresponding to the distribution of neuropathological lesions. These preliminary findings suggest that CADASIL is mediated by both glial and vascular degeneration with reduced expression of IGF receptors and AAH, which regulate Notch expression and function.