Inhibition of Angiogenesis by A  Peptides

Abstract

Abeta peptides are naturally occurring peptides forming beta-sheet aggregates that constitute an integral component of senile plaques and vascular deposits in Alzheimer's disease. Since several peptides adopting a beta-sheet conformation have been shown to be anti-angiogenic, we investigated the effect of Abeta on angiogenesis. We show that in vitro, Abeta dose-dependently inhibits the formation of capillaries by human brain endothelial cells plated on Matrigel and stimulates capillary degeneration at high doses. Preparations of Abeta peptides containing a higher content of beta-sheet structures are more potently anti-angiogenic in vitro. Ex vivo, Abeta dose-dependently opposes angiogenesis in rat aortae and in human middle cerebral arteries. In vivo, Abeta dose dependently inhibits angiogenesis in the chick chorioallantoic membrane assay and suppresses bFGF-induced blood vessel formation in the corneal micropocket and Matrigel plug assays. Since angiogenesis is required for tumor growth, we explored the effect of Abeta on human glioblastoma (U87MG) and human lung adenocarcinoma (A549) tumors. We show that intra-tumoral injection of Abeta potently inhibits the growth and vascularization of human glioblastoma and human lung adenocarcinoma tumor xenografts in nude mice. Similarly to the intra-tumoral injection regimen, Abeta delivered intraperitoneally also suppressed the growth of human lung adenocarcinoma tumor xenografts. Altogether our data show that Abeta is an angiogenesis inhibitor.

Paeonol increases levels of cortical cytochrome oxidase and vascular actin and improves behavior in a rat model of Alzheimer's disease

“…Mitochondrial dysfunction and neuroinflammatory processes may lead to an excess production of harmful reactive oxygen species (Witte et al, 2010). The finding Aβ treatment resulted in diminished levels of β-actin within the cerebral vasculature is in accord with a report that Aβ peptides are anti-angiogenic both in vitro and in vivo (Paris et al 2004). It has been reported that the cerebral vasculature is compromised in the AD brain (Blass et al 2002).…”

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

“…Similar activities have been reported for Ab, which inhibits cerebral blood flow, counteracts acetylcholine activity on blood vessels, inhibits angiogenesis and is cytotoxic for endothelial cells. 51,52 The effect of Ab on cell surface-associated ATP synthase complex in endothelial cells may account for the cerebral amyloid angiopathy aspect of Alzheimer's disease pathology.…”

Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors

“…Human middle cerebral artery endothelial cells (5 Â 10 4 ) (Paris et al, 2004) were seeded on the Matrigel in 1 ml of EBM containing VEGF (20 ng/ml). The cells were incubated in the presence or absence of GFB-204 at the concentrations indicated in the figure legend.…”