Molecular and functional dissection of TGF-β1-induced cerebrovascular abnormalities in transgenic mice
Molecular and functional dissection of TGF-β1-induced cerebrovascular abnormalities in transgenic mice
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DOI：
10.1111/j.1749-6632.2002.tb04801.x
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Wyss-Coray, T
中科院分区：
文献类型：
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作者：
Buckwalter, M;Pepper, JP;Wyss-Coray, T
脑血管异常，如血流量减少、微血管纤维化和脑血管淀粉样血管病，在阿尔茨海默病 (AD) 中很突出。然而，人们对它们的病因知之甚少，也不清楚在没有神经退行性病变的情况下，脑血管变化是否会导致功能障碍。在患有 AD 的人类中，中额叶回旋中的转化生长因子-β1 (TGF-β1) mRNA 水平与该大脑区域脑血管淀粉样蛋白沉积的相对程度呈正相关，这表明 TGF-β1 在人类脑血管异常中可能发挥作用。在星形胶质细胞中过度表达TGF-β1的转基因小鼠会出现类似AD的脑血管异常，包括血管周围星形细胞增多、微血管基底膜增厚以及在没有实质变性的情况下硫黄素S阳性淀粉样蛋白的积累。单独过度表达TGF-β1或与人淀粉样前体蛋白（hAPP）联合过度表达的小鼠表现出人β-淀粉样蛋白（Abeta）在血管中的选择性积累，并在老年时出现脑出血。在 9 个月大的 TGF-β1 转基因小鼠中，边缘系统的脑血流量 (CBF) 显着低于非转基因同窝对照小鼠。作为大脑活动的衡量标准，衰老的 TGF-β1 小鼠还表现出大脑葡萄糖摄取（CGU）总体降低。因此，大脑中 TGF-β1 的长期过量产生会导致结构和功能损伤，类似于患有淀粉样血管病的 AD 病例。
Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyros correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S-positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-beta1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.