Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells
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Published on: June 20, 2017
Daniel Paris1, Ghania Ait-Ghezala, Venkatarajan S Mathura
1The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. dparis@rfdn.org
Abstract:
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.
Insights
The Dutch A(beta) peptide, linked to hereditary cerebral hemorrhage, more potently inhibits new blood vessel formation than wild type A(beta). This suggests a key role for Dutch A(beta) in cerebrovascular pathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Vascular Biology
Background:
- Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis-Dutch type.
- Wild type amyloid-beta (A(beta)) peptides exhibit anti-angiogenic properties, potentially contributing to cerebrovascular damage in AD.
Purpose of the Study:
- To investigate the anti-angiogenic activity of the Dutch A(beta)(1-40) (E22Q) peptide.
- To compare the anti-angiogenic potency of Dutch A(beta) with wild type A(beta).
Main Methods:
- In vitro assessment of capillary structure formation by human brain microvascular endothelial cells.
- Oligonucleotide microarray analysis to identify gene networks affected by Dutch A(beta).
- Genome-scale computational analysis using the Ingenuity Pathways Knowledge Base.
Main Results:
- Freshly solubilized Dutch A(beta) peptide more potently inhibited capillary formation than wild type A(beta).
- Aggregated/fibrillar forms of both A(beta) types lacked anti-angiogenic activity in this assay.
- Dutch A(beta)'s enhanced activity correlated with increased low molecular weight A(beta) oligomers.
Conclusions:
- Dutch A(beta) peptide exhibits stronger anti-angiogenic effects than wild type A(beta), primarily through soluble oligomers.
- Exposure to Dutch A(beta) disrupts key biological networks, including those involved in angiogenesis, tumorigenesis, and cellular processes.
- These findings offer molecular insights into the pathological mechanisms of Dutch A(beta) in the cerebrovasculature.
