Poster Presentation 22nd Annual Lorne Proteomics Symposium 2017

The Glaucomic eye: A window into the molecular basis of Alzheimer’s disease  (#206)

Mehdi Mirzaei 1 , Vivek Gupta 2 , Joel M Chick 3 , Veer B Gupta 4 , Nady Braidy 5 , Yunqi Wu 6 , Todd M Greco 7 , Paul A Haynes 6 , Steven P Gygi 3 , Stuart L Graham 2
  1. Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
  2. Faculty of Medicine and Health Sciences,, Macquarie University, Sydney, NSW, Australia
  3. Department of Cell Biology, Harvard Medical School, Boston, MA, United States
  4. School of Medical Sciences, Edith Cowan University, Perth, WA, Australia
  5. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, , University of New South Wales, SYDNEY, NSW, Australia
  6. Macquarie University, Sydney, NSW, Australia
  7. Department of Molecular Biology, Princeton University, Princeton , New Jersey , USA

The association of glaucoma with Alzheimer’s disease (AD) has been postulated by several recent studies. Both diseases are neurodegenerative, chronic, and present as a continuum. Also, diagnosis is poor in the early, rather than later, stages of the disease process. We have previously demonstrated that AD is associated with ocular deficits including retinal thinning and reduced electrophysiological response. However, the molecular basis of this link remains obscure. This study was designed to elucidate the association between glaucoma and AD by investigating glaucoma-associated protein changes in the retina and vitreous humour. We performed multiplexed proteomics (TMT labelling) using the SPS-MS3 method on an Orbitrap Fusion mass spectrometer on retinal tissue and vitreous humour fluid collected from 12 glaucoma patients and 12 age-matched healthy controls. Detailed functional and protein-protein interaction analyses were performed using complementary pathway analysis tools.  We observed the differential regulation of 51 and 105 proteins, in retinal and vitreous tissues, respectively, that are in functional networks associated with AD pathology. Moreover, the differential expression of selected "research only" AD biomarkers were further evaluated using Mesoscale Discovery 96-Well MULTI-SPOT assay platform and western blotting. Taken together, our findings are in strong agreement with the inverse Warburg Hypothesis, which suggests that glaucoma and AD occur in response to mitochondrial dysfunction and metabolic reprogramming. Moreover, the classical complement pathway appears to be activated in both glaucoma and AD, suggesting a common innate inflammatory response in both disorders. Our data provides the first biochemical evidence that may explain the pathological similarities and differences between glaucoma and AD. It also provides renewed understanding of the roles of neuro-energetics in the aetiology and pathogenesis of age related neurodegenerative diseases.