June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Amyloid beta promotes retinal microvascular angiopathy through suppression of endothelial nitric oxide synthase activity: implication for retinal neurodegeneration
Author Affiliations & Notes
  • Folami Lamoke
    Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA
  • Matthew West
    Department of Ophthalmology, Medstar Georgetown University- Washington Hospital Center, Washington, DC
  • Sean Shaw
    Ophthalmology, Georgia Regents University, Augusta, GA
  • Pamela M Martin
    Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA
  • Manuela Bartoli
    Ophthalmology, Georgia Regents University, Augusta, GA
  • Footnotes
    Commercial Relationships Folami Lamoke, None; Matthew West, None; Sean Shaw, None; Pamela Martin, None; Manuela Bartoli, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3383. doi:
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      Folami Lamoke, Matthew West, Sean Shaw, Pamela M Martin, Manuela Bartoli; Amyloid beta promotes retinal microvascular angiopathy through suppression of endothelial nitric oxide synthase activity: implication for retinal neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3383.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Deposition of Amyloid beta peptides (A) has been shown to contribute to blinding diseases such as age-related macular degeneration and glaucoma. Most of the pathological effects of Abeta have been attributed to its neurotoxic properties, however, Abeta-induced cerebrovascular injury in Alzheimer’s disease (AD) has been shown to significantly contribute to its neurodegenerative effects. Therefore, here we wanted to investigate the effects of Abeta on the retinal vasculature, particularly focusing on its effect on endothelial-derived nitric oxide (NO) production.

Methods: Transgenic mice (Mo/HuAPPSwe/PS1Delta E9) overexpressing Abeta were examined at different ages. Abeta deposition was imaged by immunohistochemical detection of Thioflavin S and Congo Red staining. Blood vessels were identified by immunostaining with isolectin B4. Production of NO was measured by the fluorescent probe DAF-DA. Nitrotyrosine was assessed by immunostaining. Human retinal endothelial cells (huREC) were incubated with oligomers of Abeta1-42 and the reverse control peptide, Abeta42-1 for 48 hours at the concentration of 5μM. Agonist-mediated (VEGF20ng/ml) activation of eNOS and its activating enzyme Akt, was assessed by Western blotting detection of phospho-eNOS (Ser 1179) and phospho-Akt (Ser 473). Binding of eNOS with its constituents HSP90 and Akt was measuring by immunoprecipitation analysis.

Results: Retinas of transgenic mice showed marked Abeta deposition around retinal blood vessels which correlated with loss of DAF-DA -specific fluorescence and loss of eNOS-SerP. Treatments of huREC with Abeta promoted the constitutive association of HSP90 with eNOS, but abrogated agonist (VEGF)-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS. Furthermore, Ab blunted NO production in huREC, as shown by a significant decrease in DAF-DA -fluorescent probe.

Conclusions: The obtained results show that deposition of Abeta results in retinal vessel dysfunction characterized by a significant loss of endothelium-derived NO. Therefore, our data suggests a potential contributing role for retinal microangiopathy in ocular diseases involving enhanced Abeta deposition.

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