Wyss-Coray T, Lin C, von Euw D, Masliah E, Mucke L, Lacombe P
Gladstone Institute of Neurological Disease, University of California, San Francisco 94141, USA.
Ann N Y Acad Sci. 2000 Apr;903:317-23. doi: 10.1111/j.1749-6632.2000.tb06382.x.
Alzheimer's disease (AD) is frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. To characterize the temporal relationship between amyloid deposition, cerebrovascular abnormalities, and potential functional changes, we studied transgenic mice that express transforming growth factor-beta 1 (TGF-beta 1) at low levels in astrocytes. TGF-beta 1 induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. Associated with these morphological changes were changes in regional cerebral glucose utilization. Preliminary results showed that TGF-beta 1 mice had significantly decreased glucose utilization in the mammillary bodies, structures involved in mnemonic and learning processes. Glucose utilization tended to be decreased in several other brain regions as well; however, in the inferior colliculus, it was markedly higher in TGF-beta 1 mice than in controls. We conclude that chronic overproduction of TGF-beta 1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity. Similar mechanisms may be involved in AD pathogenesis.
阿尔茨海默病（AD）常与脑血管变化相关，包括血管周围星形细胞增生、淀粉样蛋白沉积和微血管变性，但尚不清楚这些病理变化是否导致AD的功能缺陷。为了描述淀粉样蛋白沉积、脑血管异常和潜在功能变化之间的时间关系，我们研究了在星形细胞中低水平表达转化生长因子β1（TGF-β1）的转基因小鼠。TGF-β1诱导了显著的血管周围星形细胞增生，随后微血管中基底膜蛋白积累、毛细血管基底膜增厚，随后在大约6个月大时，淀粉样蛋白在脑血管中沉积。在9个月大时，在内皮细胞和周细胞中观察到各种类似AD的退行性改变。与这些形态学变化相关的是局部脑葡萄糖利用的变化。初步结果表明，TGF-β1小鼠乳头体（参与记忆和学习过程的结构）的葡萄糖利用显著降低。其他几个脑区的葡萄糖利用也有降低的趋势；然而，在中脑下丘，TGF-β1小鼠的葡萄糖利用明显高于对照组。我们得出结论，TGF-β1的慢性过量产生引发了一个致病级联反应，导致类似AD的脑血管淀粉样变性、微血管变性和脑代谢活动的局部改变。AD发病机制可能涉及类似的机制。
