Effect of SU5416, an inhibitor of angiogenesis, on processing of the beta-amyloid precursor protein in primary neuronal and astrocytic cells derived from brain tissue of Tg2576 mice

Abstract

A large number of Alzheimer patients demonstrate cerebrovascular pathology, and functional vascular abnormalities are one of the earlier clinical manifestations in Alzheimer's disease (AD). There are a number of studies providing evidence that the cerebrovascular degenerations in AD are 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. The upregulation of VEGF in response to hypoxic, or ischemic stress, suggests its involvement also in processing of the amyloid precursor protein (APP). To test whether inhibition of angiogenesis may affect APP processing, primary neuronal and astrocytic cells derived from transgenic Tg2576 mice that over express the Swedish mutation of human APP, were exposed by the VEGF receptor antagonist and inhibitor of angiogenesis, SU5416, and the effects of SU5416 on APP metabolism were examined. Exposure of primary neuronal cells by SU5416 for 24 hours resulted in increased release of sAPPβ, and strikingly enhanced secretion of Aβ(1-40) and Aβ(1-42) into the culture medium, which was accompanied by a significant increase in β-secretase activity, as compared to control incubations. In contrast, incubation of primary astrocytes in the presence of SU5416 for 24h resulted in decreased secretion of Aβ(1-40) and Aβ(1-42), and sAPPβ into the culture medium, as compared to control incubations. The SU5416-induced effects on APP processing could not be suppressed by the additional presence of VEGF, sugesting that SU5416 affects pathways that are apparently independent of VEGF receptor signaling. The data obtained indicate that the angiogenesis inhibitor SU5416 may affect APP processing but differentially acting in neurons and astrocytes.The data further suggest a link of angiogenesis and pathogenesis of Alzheimer's disease.