Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L
Gladstone Molecular Neurobiology Program and Department of Neurology, University of California, San Francisco 94141-9100, USA.
Nature. 1997 Oct 9;389(6651):603-6. doi: 10.1038/39321.
Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.
β-淀粉样肽在中枢神经系统中的沉积是阿尔茨海默病的一个标志，也是神经退行性变的一个可能原因。引发或促进β-淀粉样肽沉积的因素尚不清楚。转化生长因子TGF-β1在大脑对损伤的反应中起核心作用，并且在阿尔茨海默病患者的中枢神经系统中发现TGF-β1水平升高。在此我们报告，TGF-β1在老年转基因小鼠的脑血管和脑膜中诱导β-淀粉样蛋白沉积，这些转基因小鼠从星形胶质细胞过度表达这种细胞因子。在过度表达淀粉样前体蛋白且出现类似阿尔茨海默病病理的转基因小鼠中，TGF-β1的共表达加速了β-淀粉样肽的沉积。与对照组相比，阿尔茨海默病患者死后脑组织中存在更多的TGF-β1信使核糖核酸，其水平与患有脑淀粉样血管病患者受损脑血管中的β-淀粉样蛋白沉积密切相关。这些结果表明，TGF-β1的过度表达可能在阿尔茨海默病及其实验模型中引发或促进淀粉样蛋白生成，因此可能是患阿尔茨海默病的一个风险因素。
