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

Jul 11, 2009International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience

VEGF influences amyloid protein processing and buildup in brain tissue from Alzheimer's model mice

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Abstract

VEGF exposure for 6 hours reduced soluble Abeta(1-40) and Abeta(1-42) levels in brain slices from Tg2576 mice.

No significant changes in the expression level of amyloid precursor protein (APP) were observed after VEGF exposure for any duration.
The reduction in soluble Abeta levels was accompanied by a temporary decrease in beta-secretase activity, with the peak effect at 6 hours.
After 24 hours of VEGF exposure, the effect on Abeta formation was less pronounced, and it was no longer detectable after 72 hours.
VEGF slightly decreased the fibrillar content of Abeta with increasing incubation time, indicating a potential influence on Abeta fibrillogenesis.
These findings suggest that VEGF may play a role in amyloid processing, which could be relevant to Alzheimer's disease pathogenesis.

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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.

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

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