Effect of VEGF and its receptor antagonist SU-5416, an inhibitor of angiogenesis, on processing of the beta-amyloid precursor protein in primary neuronal cells derived from brain tissue of Tg2576 mice.

International journal of developmental neuroscience : the official journal of the International Soci 2010 Jul 22; In press

Bürger S, Yafai Y, Bigl M, Wiedemann P, Schliebs R

Paul Flechsig Institute for Brain Research, Medical Faculty, University of Leipzig.

A large number of Alzheimer patients demonstrate cerebrovascular pathology, which has been assumed to be related to beta-amyloid (Abeta) deposition. Abeta 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 1ng/ml VEGF for six, 12, and 24hours, followed by monitoring formation and secretion of soluble Abeta peptides, release of the human APP cleavage products, sAPPbetaswe and sAPPalpha, into the culture medium as well as the activities of alpha- and beta-secretases in neuronal cell extracts. Exposure of primary neuronal cells by VEGF for 24hours led to slightly reduced sAPPbeta release, accompanied by decreased beta-secretase activity 12h after VEGF exposure. Incubation of neurons by the VEGF receptor antagonist and angiogenesis inhibitor SU-5416 for 24hours resulted in increased release of sAPPbetaswe, and strikingly enhanced secretion of Abeta peptides into the culture medium, which was accompanied by a significant increase in beta-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, sugesting 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 Alzheimers disease.

Keywords: VEGF SU-5416 angiogenesis amyloid Alzheimer