June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Age-related beta-Synculein alters the p53/MDM-2 pathway and induce apoptosis within Brain-Microvascular Endothelial Cells in-vitro
Author Affiliations & Notes
  • MIchael Böhm
    Department of Ophthalmology, Essen University Hospital, Essen, Germany
    Institute for Experimental Ophthalmology, School of Medicine, Westfalian Wilhelms-University Muenster, Muenster, Germany
  • Katrin Brockhaus
    Institute for Experimental Ophthalmology, School of Medicine, Westfalian Wilhelms-University Muenster, Muenster, Germany
  • Harutyn Melkonyan
    Institute for Experimental Ophthalmology, School of Medicine, Westfalian Wilhelms-University Muenster, Muenster, Germany
  • Klaus-Peter Steuhl
    Department of Ophthalmology, Essen University Hospital, Essen, Germany
  • Solon Thanos
    Institute for Experimental Ophthalmology, School of Medicine, Westfalian Wilhelms-University Muenster, Muenster, Germany
  • Footnotes
    Commercial Relationships   MIchael Böhm, Novartis Pharma GmbH, Nürnberg, Germany (R); Katrin Brockhaus, None; Harutyn Melkonyan, None; Klaus-Peter Steuhl, None; Solon Thanos, Novartis Pharma GmbH, Nürnberg, Germany (R)
  • Footnotes
    Support  Grant of the German Research Foundation (DFG Grant BO 4556/1-1)
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5861. doi:
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      MIchael Böhm, Katrin Brockhaus, Harutyn Melkonyan, Klaus-Peter Steuhl, Solon Thanos; Age-related beta-Synculein alters the p53/MDM-2 pathway and induce apoptosis within Brain-Microvascular Endothelial Cells in-vitro. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5861.

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

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Abstract

Purpose : Increased beta-synuclein (SNCB) has been previoiusly described within the aging visual system including neuroretina and primary visual cortex. SNCB functions as physiological antagonist of alpha-synuclein (SNCA), which is involved in neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. How ever, the exact function of SNCB is already unknown. Brain-microvascular endothelial cells (BMECs) maintain physiological homeostasis and support studies about the blood-brain barrier within the neurovascular unit. Aim of this study was elucidate the age-dependend role of SNCB within endothelial cells of the neurovascular unit of rats.

Methods : BMECs were isolated from cortices of 5-9 days old Sprague-Dawley rats and were cultured with different concentrations of recombinant SNCB (rSNCB) up to 72h. Viability (MTT), apoptosis (TUNEL) and expression levels of SNCA, members of the Poshpolipase D2 (PLD2) - p53 - MDM-2 - p19-ARF pathway, response to AKT, and stress mediated factors like HMOX and NOX4 were studied by using immunohistochemistry (IF), Western blot (WB), and qRT-PCR. Related effects of rSNCB were confirmed by inducing SNCB knock-down via siRNA within BMECs.

Results : BMECs revealed a decreased viability and increased apoptosis after SNCB exposure. Decreased protein- and mRNA expression levels of SNCA have been found. IF and WB analysis indicate an inhibition of Akt together with an elevation of PLD2, activation of p53, endorced intracellular MDM2 translocation and elevated p19-ARF. More over, an elevation of PLD2 activity in SNCB exposed BMECs has been found. Alterations of HMOX and Nox4 indicate a stress related response of BMECs exposed to SNCB.

Conclusions : The presented results indicate a distinct effect of SNCB on BMECs in-vitro. Due to a p53 mediated and Akt independent apoptosis together with a stress mediated response of BMECs may be induced by increasing SNCB with age in the neurovascular unit. Further studies on the molecular mechanisms based on age-depending role of SNCB may help to increase understanding about neurodegenerative diseases. Supported by the German Research Foundation (DFG, BO 4556/1-1)

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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