Dutch and arctic mutant peptides of {beta} amyloid{sub 1-40} differentially affect the FGF-2 pathway in brain endothelium
- Department of Molecular Biology, University of Siena, Via A. Moro 2, 53100, Siena (Italy)
- Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016 (United States)
Single point mutations of the amyloid precursor protein generate A{beta} variants bearing amino acid substitutions at positions 21-23. These mutants are associated with distinct hereditary phenotypes of cerebral amyloid angiopathy, manifesting varying degrees of tropism for brain vessels, and impaired microvessel remodeling and angiogenesis. We examined the differential effects of E22Q (Dutch), and E22G (Arctic) variants in comparison to WT A{beta} on brain endothelial cell proliferation, angiogenic phenotype expression triggered by fibroblast growth factor (FGF-2), pseudo-capillary sprouting, and induction of apoptosis. E22Q exhibited a potent anti-angiogenic profile in contrast to E22G, which had a much weaker effect. Investigations on the FGF-2 signaling pathway revealed the greatest differences among the peptides: E22Q and WT peptides suppressed FGF-2 expression while E22G had barely any effect. Phosphorylation of the FGF-2 receptor, FGFR-1, and the survival signal Akt were abolished by E22Q and WT peptides, but not by E22G. The biological dissimilar effect of the mutant and WT peptides on cerebral EC cannot be assigned to a particular A{beta} structure, suggesting that the toxic effect of the A{beta} assemblies goes beyond mere multimerization.
- OSTI ID:
- 21176166
- Journal Information:
- Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 3 Vol. 315; ISSN 0014-4827; ISSN ECREAL
- Country of Publication:
- United States
- Language:
- English
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