Biochim Biophys Acta. 2014 Sep;1842(9):1567-78.

BDNF impairment is associated with age-related changes in the inner retina and exacerbates experimental glaucoma.

 

Gupta V1, You Y2, Li J2, Gupta V3, Golzan M2, Klistorner A4, van den Buuse M5, Graham S4.
  • 1Australian School of Advanced Medicine, Macquarie University, Australia. Electronic address: vivek.gupta@mq.edu.au.
  • 2Australian School of Advanced Medicine, Macquarie University, Australia.
  • 3School of Medical Sciences, Edith Cowan University, Perth, Australia.
  • 4Australian School of Advanced Medicine, Macquarie University, Australia; Save Sight Institute, Sydney University, Australia.
  • 5Behavioural Neuroscience Laboratory, Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Department of Pharmacology, University of Melbourne, Australia; School of Psychological Science, La Trobe University, Melbourne, Australia.

 

Abstract

Brain-derived neurotrophic factor (BDNF) stimulation of its high-affinity receptor TrkB results in activation of pro-survival cell-signalling pathways that can afford neuroprotection to the retina. Reduction in retrograde axonal transport of neurotrophic factors such as BDNF from the brain to the neuronal cell bodies in the retina has been suggested as a critical factor underlying progressive and selective degeneration of ganglion cell layer and optic nerve in glaucoma. We investigated the role of BDNF in preserving inner retinal homeostasis in normal and glaucoma states using BDNF(+/-) mice and compared it with wild type controls. This study demonstrated that BDNF(+/-) animals were more susceptible to functional, morphological and molecular degenerative changes in the inner retina caused by age as well as upon exposure to experimental glaucoma caused by increased intraocular pressure. Glaucoma induced a down regulation of BDNF/TrkB signalling and an increase in levels of neurotoxic amyloid β 1-42 in the optic nerve head which were exacerbated in BDNF(+/-) mice. Similar results were obtained upon analysing the human optic nerve head tissues. Our data highlighted the role of BDNF in maintaining the inner retinal integrity under normal conditions and the detrimental effects of its insufficiency on the retina and optic nerve in glaucoma.

KEYWORDS: Amyloid beta; Brain-derived neurotrophic factor; Ganglion cell layer; Glaucoma; Signal transduction; TrkB receptor

PMID: 24942931

 

Supplement:

Brain derived neurotrophic factor (BDNF) is a critical for the neuronal survival and axonal growth of the cells in the central nervous system. Several studies have suggested the important role that BDNF and its high affinity receptor Tropomyosin receptor kinase B (TrkB) play in the survival of retinal ganglion cells in the retina (1, 2). The role of BDNF in the inner retina was tested in vivo using BDNF+/- mice using a series of biochemical and electrophysiological experiments. Our studies showed a decline in the inner retinal function of these animals with age. Concurrently a decrease in the density of ganglion cells was also observed in the retina. These findings suggested that BDNF plays an important role in the preservation of inner retinal structure and function. Interestingly, we also observed enhanced accumulation of the amyloid β peptide in the retina with age. In order to further test whether BDNF/TrkB plays any role in glaucoma conditions, we overlaid the BDNF+/- mice with the experimental increase in intraocular pressure using microbead injections into the eye. Results showed that these animals depicted greater structural and functional deterioration of the inner retina compared to wild type animals thereby indicating that BDNF might play a critical role in the glaucoma pathogenesis. A novel observation was a reduction in the Glycogen synthase kinase-3 β (GSK3β) phosphorylation (Ser9) both in the animal models of glaucoma as well as in human donor glaucoma tissues. Further investigations unraveled that the loss of BDNF is associated with GSK3β deposphorylation leading to its activation (3). An increase in the amyloid β peptide was also observed in experimental models of glaucoma, but the increase was much more prominent in the BDNF+/- mice compared to the controls. Downregulation of BDNF/TrkB has previously been reported in Alzheimer’s disease. This study is significant for elucidating the roles of BDNF/TrkB signaling in the inner retina in normal as well as in glaucoma conditions. It also validates previous observations that BDNF downregulation promotes amyloid β production in the brain. As retina is a part of the central nervous system these findings may greatly help us to understand the shared pathological mechanisms underlying amyloid β accumulation in the retina and brain under various neurodegenerative conditions.

 

References

1. V.K. Gupta, Y. You, J Li, V Gupta, M Golzan, A. Klistorner, M van den Buuse, S.L. Graham (2014) BDNF impairment is associated with age-related changes in the inner retina and exacerbates experimental glaucoma. Biochim Biophys Acta. 1842 (9): 1567-78.

2.V.K. Gupta, Y. You, A. Klistorner, S.L. Graham (2012) Shp-2 regulates the TrkB receptor activity in the retinal ganglion cells under glaucomatous stress. Biochim. Biophys. Acta. (1822), 1643–1649

3.V.K. Gupta, N. Chitranshi, Y. You, V. Gupta, A. Klistorner, S.L. Graham (2014) Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β) signalling. Biochem Biophys Res Commun. 454 (3):381-386.
 

VG FIG1Contact:

Dr. Vivek Gupta Faculty of Medicine and Health Sciences Macquarie University, NSW, Australia 2109.

 

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