Brain Res Mol Brain Res.
2005 May 20;136(1-2):212-30.
Anti-angiogenic
activity of the mutant Dutch A(beta) peptide on human
brain microvascular endothelial cells.
Paris D, Ait-Ghezala G, Mathura VS, Patel N, Quadros A, Laporte V, Mullan M.
The Roskamp Institute,
Cerebral amyloid angiopathy
is a common pathological feature of patients with Alzheimer's disease (AD) and
it is also the hallmark of individuals with a rare autosomal
dominant disorder known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. We have shown previously that wild
type A(beta) peptides are anti-angiogenic
both in vitro and in vivo and could contribute to the compromised cerebrovascular architecture observed in AD. In the present
study, we investigated the potential anti-angiogenic
activity of the Dutch A(beta)(1-40) (E22Q) peptide. We
show that compared to wild type A(beta), freshly solubilized
Dutch A(beta) peptide more potently inhibits the formation of capillary
structures induced by plating human brain microvascular
endothelial cells onto a reconstituted basement membrane. Aggregated/fibrillar preparations of wild type A(beta)
and Dutch A(beta) do not appear to be anti-angiogenic
in this assay. The stronger anti-angiogenic activity
of the Dutch A(beta) compared to wild type A(beta)
appears to be related to the increased formation of low molecular weight
A(beta) oligomers in the culture medium surrounding
human brain microvascular endothelial cells. Using oligonucleotide microarray
analysis of human brain microvascular endothelial
cells, followed by a genome-scale computational analysis with the Ingenuity
Pathways Knowledge Base, networks of genes affected by an anti-angiogenic dose of Dutch A(beta) were identified. This
analysis highlights that several biological networks involved in angiogenesis, tumorigenesis, atherosclerosis, cellular migration and
proliferation are disrupted in human brain microvascular
endothelial cells exposed to Dutch A(beta).
Altogether, these data provide new molecular clues regarding the pathological
activity of Dutch A(beta) peptide in the cerebrovasculature.
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Keywords: Anti-angiogenic, mutant, Dutch A(beta), microvascular, endothelial, Molecular Brain Research