June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Oxidative stress-induced ADAM10 and BACE1 imbalance leads to amyloid beta (Abeta) production in retinal pigment epithelial cells (RPE)
Author Affiliations & Notes
  • ABDELSALAM SHARKASI
    Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Shivani Kumaresan
    Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Ravirajsinh Jadeja
    Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Pamela M Martin
    Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Menaka Thounaojam
    Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Manuela Bartoli
    Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   ABDELSALAM SHARKASI, None; Shivani Kumaresan, None; Ravirajsinh Jadeja, None; Pamela Martin, None; Menaka Thounaojam, None; Manuela Bartoli, None
  • Footnotes
    Support  Medical Scholars Program and the Department of Ophthalmology at Augusta University
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2259. doi:
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      ABDELSALAM SHARKASI, Shivani Kumaresan, Ravirajsinh Jadeja, Pamela M Martin, Menaka Thounaojam, Manuela Bartoli; Oxidative stress-induced ADAM10 and BACE1 imbalance leads to amyloid beta (Abeta) production in retinal pigment epithelial cells (RPE). Invest. Ophthalmol. Vis. Sci. 2020;61(7):2259.

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

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Abstract

Purpose : Deposition of amyloid beta peptides (Aβ) in drusen can have detrimental effects on vision and has been involved in the pathogenesis of age-related macular degeneration (AMD). The molecular mechanisms of Aβ generation in retinal pigmented epithelial cells (RPE) is poorly understood, but could be relevant to the treatment of AMD. Aβ results from the cleavage of a larger amyloid precursor protein (APP) by β- and γ-secretases. BACE-1 (β-site APP-cleaving enzyme 1) is the rate-limiting factor in Aβ generation. On the other hand, APP cleavage by ADAM10 results in the production of APP-derived fragment, sAPP, which is neuroprotective. Here we have investigated the effects of oxidative stress, a key AMD pathogenic factor, on the regulation of expression and activity of ADAM10 and BACE1.

Methods : Oxidative stress was induced in human retinal pigment epithelial cells (HuRPE) by treatment with different doses of tert-Butyl Hydroperoxide (tBHP) or sodium iodate (SI) for 24, 48 or 72 hr. mRNA and protein expression of APP, BACE1 and ADAM10 were evaluated by qPCR and Western blot respectively. Mouse RPE cells were isolated from 17days mouse pups, cultured and treated with 5 and 10 mM SI for 48 or 72 hr. APP, ADAM10 and BACE1 specific mRNAs were evaluated by qPCR. Eight weeks old C57BL/6J mice were treated with 50 mg/kg SI (i.p. once) and RPE/eye cup were dissected at 1, 3, 7 and 14 days post treatment to assess APP, BACE1 and ADAM10 mRNA and protein levels.

Results : HuRPE cells treated with different doses of both tBHP and SI showed increased mRNA and protein expression of APP and BACE 1. These effects were accompanied by decreased ADAM10 expression. In primary mouse RPE treated with both SI and tBHP, ADAM10 was downregulated, while BACE1 and APP were upregulated. RPE from SI-injected mice displayed APP, BACE1 and ADAM10 expression pattern similar to that seen in the isolated cells with increased levels of APP and BACE1, but decreased ADAM10 in comparison to vehicle-treated mice retinas.

Conclusions : Collectively, our data shows that RPE can directly produce Abeta and oxidative stress plays a pivotal role in this process, by altering ADAM10 and BACE1 expression pattern, therefore switching the balance in favor of the amyloidogenic pathway. Strategies aimed at reducing oxidative stress or restoring ADAM10 function could have great beneficial effects for treating AMD.

This is a 2020 ARVO Annual Meeting abstract.

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