Research Paper Volume 9, Issue 4 pp 1248—1268

Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence

Lucinda S. McRobb 1, , Matthew J. McKay 2, , Jennifer R. Gamble 3, , Michael Grace 4, , Vaughan Moutrie 4, , Estevam D. Santos 4, , Vivienne S. Lee 1, , Zhenjun Zhao 1, , Mark P. Molloy 2, , Marcus A. Stoodley 1, ,

  • 1 Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia
  • 2 Australian Proteome Analysis Facility, Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia
  • 3 Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, New South Wales, 2042, Australia
  • 4 Genesis Cancer Care, Macquarie University Hospital, Sydney, New South Wales, 2109, Australia

received: February 28, 2016 ; accepted: April 10, 2017 ; published: April 17, 2017 ;
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Cellular senescence is associated with aging and is considered a potential contributor to age-associated neurodegenerative disease. Exposure to ionizing radiation increases the risk of developing premature neurovascular degeneration and dementia but also induces premature senescence. As cells of the cerebrovascular endothelium are particularly susceptible to radiation and play an important role in brain homeostasis, we investigated radiation-induced senescence in brain microvascular endothelial cells (EC). Using biotinylation to label surface proteins, streptavidin enrichment and proteomic analysis, we analyzed the surface proteome of stress-induced senescent EC in culture. An array of both recognized and novel senescence-associated proteins were identified. Most notably, we identified and validated the novel radiation-stimulated down-regulation of the protease, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 is an important modulator of amyloid beta protein production, accumulation of which is central to the pathologies of Alzheimer’s disease and cerebral amyloid angiopathy. Concurrently, we identified and validated increased surface expression of ADAM10 proteolytic targets with roles in neural proliferation and survival, inflammation and immune activation (L1CAM, NEO1, NEST, TLR2, DDX58). ADAM10 may be a key molecule linking radiation, senescence and endothelial dysfunction with increased risk of premature neurodegenerative diseases normally associated with aging.


Ab: amyloid beta; AD: Alzheimer's disease; ADAM10: a disintegrin and metalloproteinase-domain containing protein 10; APP: amyloid precursor protein; BACE-1: beta-site amyloid precursor protein cleaving enzyme 1; BSA: bovine serum albumin; CAA: cerebral amyloid angiopathy; DAMP: damage-associated molecular pattern; DDX58: dead box protein 58/RIG-1-like receptor 1, EC, endothelial cell; FDR: false discovery rate, Gy, Gray; IR: ionizing radiation; L1CAM: neural cell adhesion molecule 1; L3CB: microtubule-associated protein 1 light chain 3 beta, LC/MS, liquid chromatography-mass spectrometry; LINAC: linear accelerator; NEO1: neogenin 1; NEST: nestin; SA-b-gal: senescence-associated beta-galactosidase; SASP: senescence-associated secretory phenotype; SWATH: sequential window acquisition of all theoretical mass spectra; TLR2: toll-like receptor 2.