PURPOSE: Amyloid-beta (Aβ) is an endogenous peptide that becomes dysregulated in AMD and Alzheimer disease. Both of these disorders are marked by extracellular deposits that contain Aβ, highly branched capillary networks, and neurodegeneration. Although Aβ has been implicated in AMD and Alzheimer pathology for decades, its nonpathological function has remained unclear. We recently showed that high levels of monomeric Aβ induce blood vessel branching in embryonic zebrafish brain, and here we report that a similar mechanism may contribute to aberrant blood vessel branching in the retina of adult zebrafish. METHODS: Transgenic zebrafish expressing enhanced green fluorescence protein (EGFP) in their endothelial cells were sedated and small intraocular injections of PBS were made into one eye and either Aβ or γ-secretase inhibitor were injected into their opposite eye. A week later, the eyes were enucleated and high resolution maps of the retina vasculature were created using confocal microscopy. Comparisons were made between the treatment groups using the general linear model ANOVA. RESULTS: We found that Aβ significantly affects capillary blood vessels in the retina. Small volumes of Aβ injected into the eyes of adult zebrafish induced the formation of significantly more endothelial tip cells and capillary bridges-some with loops-near the circumferential vein. These effects were dose-dependent and increased capillary bed density, though there was no effect on larger arterial vessels. CONCLUSIONS: This study reveals a previously unknown role for Aβ in regulating capillary bed density, providing new insight into the normal biological function. Aβ will help in the development of therapeutic interventions for AMD and Alzheimer disease.
PURPOSE: Amyloid-beta (Aβ) is an endogenous peptide that becomes dysregulated in AMD and Alzheimer disease. Both of these disorders are marked by extracellular deposits that contain Aβ, highly branched capillary networks, and neurodegeneration. Although Aβ has been implicated in AMD and Alzheimer pathology for decades, its nonpathological function has remained unclear. We recently showed that high levels of monomeric Aβ induce blood vessel branching in embryonic zebrafish brain, and here we report that a similar mechanism may contribute to aberrant blood vessel branching in the retina of adult zebrafish. METHODS: Transgenic zebrafish expressing enhanced green fluorescence protein (EGFP) in their endothelial cells were sedated and small intraocular injections of PBS were made into one eye and either Aβ or γ-secretase inhibitor were injected into their opposite eye. A week later, the eyes were enucleated and high resolution maps of the retina vasculature were created using confocal microscopy. Comparisons were made between the treatment groups using the general linear model ANOVA. RESULTS: We found that Aβ significantly affects capillary blood vessels in the retina. Small volumes of Aβ injected into the eyes of adult zebrafish induced the formation of significantly more endothelial tip cells and capillary bridges-some with loops-near the circumferential vein. These effects were dose-dependent and increased capillary bed density, though there was no effect on larger arterial vessels. CONCLUSIONS: This study reveals a previously unknown role for Aβ in regulating capillary bed density, providing new insight into the normal biological function. Aβ will help in the development of therapeutic interventions for AMD and Alzheimer disease.