Vascular endothelial growth factor (VEGF) affects processing of amyloid precursor protein and β‐amyloidogenesis in brain slice cultures derived from transgenic Tg2576 mouse brain

Abstract

The up-regulation of the angiogenic vascular endothelial growth factor (VEGF) in brains of Alzheimer patients in close relationship to beta-amyloid (Abeta) plaques, suggests a link of VEGF action and processing of the amyloid precursor protein (APP). To reveal whether VEGF may affect APP processing, brain slices derived from 17-month-old transgenic Tg2576 mice were exposed with 1ng/ml VEGF for 6, 24, and 72h, followed by assessing cytosolic and membrane-bound APP expression, level of both soluble and fibrillar Abeta-peptides, as well as activities of alpha- and beta-secretases in brain slice tissue preparations. Treatment of brain slices with VEGF did not significantly affect the expression level of APP, regardless of the exposure time studied. In contrast, VEGF exposure of brain slices for 6h reduced the formation of soluble, SDS extractable Abeta(1-40) and Abeta(1-42) as compared to brain slice cultures incubated in the absence of any drug, while the fibrillar Abeta peptides did not change significantly. This effect was less pronounced 24h after VEGF exposure, but was no longer detectable when brain slices were exposed by VEGF for 72h, which indicates an adaptive response to chronic VEGF exposure. The VEGF-mediated reduction in Abeta formation was accompanied by a transient decrease in beta-secretase activity peaking 6h after VEGF exposure. To reveal whether the VEGF-induced changes in soluble Abeta-level may be due to actions of VEGF on Abeta fibrillogenesis, the fibrillar status of Abeta was examined using the thioflavin-T binding assay. Incubation of Abeta preparations obtained from Tg2576 mouse brain cortex, in the presence of VEGF slightly decreased the fibrillar content with increasing incubation time up to 72h. The data demonstrate that VEGF may affect APP processing, at least in vitro, suggesting a role of VEGF in the pathogenesis of Alzheimer's disease.

Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β Peptide Generation In Vivo

“…The possibility remains that reoxygenation after hypoxia (rather than hypoxia itself) is associated with an enhanced amyloidogenic processing of AβPP. Also, the potential indirect effects of hypoxia on Aβ metabolism, for example mediated through Vegf [41,42], were not investigated here. More studies are needed to elucidate the molecular mechanism(s) that underlie(s) the epidemiological evidence linking hypoxia and cerebrovascular ischemic disease with Alzheimer disease.…”

Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

“…Further, EGF did not modulate Aβ levels unlike VEGF in AD-Tg mice [58]. Although VEGF lowers Aβ levels in slice cultures [11] a role for EGF in this process has not been assessed. As EGF did not change Aβ levels, one hypothesis is that EGF acts directly on brain endothelial cells to prevent disrupted signaling induced by the interactive effects of female sex, APOE4 and Aβ in E4FADF mice.…”

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Microvessels isolated from the brain of AD patients express a large number of angiogenic proteins, including VEGF [164], but without evidence of vascular growth [173]. The lack of vascular response could cause a chronic state of activation of endothelial cells [174], resulting in the release of proinflammatory and potentially neurotoxic products.…”

“…Hypoxia also stimulates endothelial angiogenic proteins, including VEGF [164]. However, the lack of vascular growth in response to VEGF [173] might cause a chronic state of endothelial activation, resulting in the release of proinflammatory and potentially neurotoxic products. Hypoxia is also associated with low levels of MEOX-2 in AD, resulting in degradation of endothelial LRP-1, regression of capillary networks, and reduced cerebral microcirculation [175,176].…”