Anti-angiogenic activity of the mutant Dutch Aβ peptide on human brain microvascular endothelial cells

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 Aβ 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 Aβ1-40 (E22Q) peptide. We show that compared to wild type Aβ, freshly solubilized Dutch Aβ 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 Aβ and Dutch Aβ do not appear to be anti-angiogenic in this assay. The stronger anti-angiogenic activity of the Dutch Aβ compared to wild type Aβ appears to be related to the increased formation of low molecular weight Aβ 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 Aβ 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 Aβ. Altogether, these data provide new molecular clues regarding the pathological activity of Dutch Aβ peptide in the cerebrovasculature.