Bürger Susanne, Yafai Yousef, Bigl Marina, Wiedemann Peter, Schliebs Reinhard
Paul Flechsig Institute for Brain Research, Medical Faculty, University of Leipzig, Germany.
Int J Dev Neurosci. 2010 Nov;28(7):597-604. doi: 10.1016/j.ijdevneu.2010.07.231. Epub 2010 Jul 22.
A large number of Alzheimer patients demonstrate cerebrovascular pathology, which has been assumed to be related to β-amyloid (Aβ) deposition. Aβ peptides have been described to inhibit angiogenesis both in vitro and in vivo, and deregulation of angiogenic factors may contribute to various neurological disorders including neurodegeneration. One of the key angiogenic factor is the vascular endothelial growth factor (VEGF). Increased levels of VEGF have been observed in brains of Alzheimer patients, while the functional significance of VEGF up-regulation in the pathogenesis and progression of AD is still a matter of debate. To test whether VEGF may affect neuronal APP processing, primary neuronal cells derived from brain tissue of E16 embryos of Tg2576 mice were exposed with 1 ng/ml VEGF for 6, 12, and 24h, followed by monitoring formation and secretion of soluble Aβ peptides, release of the human APP cleavage products, sAPPβswe and sAPPα, into the culture medium as well as the activities of α- and β-secretases in neuronal cell extracts. Exposure of primary neuronal cells by VEGF for 24h led to slightly reduced sAPPβ release, accompanied by decreased β-secretase activity 12h after VEGF exposure. Incubation of neurons by the VEGF receptor antagonist and angiogenesis inhibitor SU-5416 for 24h resulted in increased release of sAPPβswe, and strikingly enhanced secretion of Aβ peptides into the culture medium, which was accompanied by a significant increase in β-secretase activity, as compared to control incubations. The SU-5416-induced effects on APP processing could not be suppressed by the additional presence of VEGF, suggesting that SU-5416 affects pathways that are apparently independent of VEGF receptor signaling. The data obtained indicate that VEGF-driven mechanisms may affect APP processing, suggesting a link of angiogenesis and pathogenesis of Alzheimer's disease.
大量阿尔茨海默病患者表现出脑血管病变，这被认为与β-淀粉样蛋白（Aβ）沉积有关。Aβ肽在体外和体内均被描述为可抑制血管生成，血管生成因子的失调可能导致包括神经退行性变在内的各种神经疾病。关键的血管生成因子之一是血管内皮生长因子（VEGF）。在阿尔茨海默病患者的大脑中观察到VEGF水平升高，而VEGF上调在AD发病机制和进展中的功能意义仍存在争议。为了测试VEGF是否可能影响神经元APP加工，将来自Tg2576小鼠E16胚胎脑组织的原代神经元细胞用1 ng/ml VEGF处理6、12和24小时，然后监测可溶性Aβ肽的形成和分泌、人APP裂解产物sAPPβswe和sAPPα释放到培养基中的情况以及神经元细胞提取物中α-和β-分泌酶的活性。用VEGF处理原代神经元细胞24小时导致sAPPβ释放略有减少，同时在VEGF处理后12小时β-分泌酶活性降低。用VEGF受体拮抗剂和血管生成抑制剂SU-5416孵育神经元24小时导致sAPPβswe释放增加，并且显著增强Aβ肽分泌到培养基中，与对照孵育相比，这伴随着β-分泌酶活性的显著增加。SU-5416对APP加工的诱导作用不能被额外存在的VEGF抑制，这表明SU-5416影响的途径显然独立于VEGF受体信号传导。所获得的数据表明，VEGF驱动的机制可能影响APP加工，提示血管生成与阿尔茨海默病发病机制之间存在联系。
