Buckwalter Marion, Pepper Jon-Paul, Gaertner Roger F, Von Euw Dominique, Lacombe Pierre, Wyss-Coray Tony
Department of Neurology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94141, USA.
Ann N Y Acad Sci. 2002 Nov;977:87-95. doi: 10.1111/j.1749-6632.2002.tb04801.x.
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 gyrus 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.
脑血管异常，如血流减少、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，它们的病因尚不清楚，并且在没有神经退行性变的情况下，脑血管变化是否导致功能障碍也不清楚。在患有AD的人类中，额中回的转化生长因子-β1（TGF-β1）mRNA水平与该脑区脑血管淀粉样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起作用。在星形胶质细胞中过表达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生、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。单独过表达TGF-β1或除了人类淀粉样前体蛋白（hAPP）之外过表达TGF-β1的小鼠在血管中显示出人β淀粉样蛋白（Aβ）的选择性积累，并在老年时发生脑出血。在9个月大的TGF-β1转基因小鼠中，边缘系统的脑血流量（CBF）明显低于非转基因同窝对照。老年TGF-β1小鼠还显示出作为脑活动指标的脑葡萄糖摄取（CGU）总体降低。因此，大脑中TGF-β1的慢性过量产生会导致结构和功能障碍，类似于伴有淀粉样血管病的AD病例中的情况。
