title: Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB.
abstract: According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies.
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Dekeyster
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Emiel
authors.initials: E
authors.lastname: Geeraerts
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Buyens
authors.affiliation: Neurobiology and Gene Therapy Research Group, Department of Neurosciences, KU Leuven, Leuven, Belgium.|Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Neurobiology and Gene Therapy Research Group, Department of Neurosciences, KU Leuven, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: De Groef
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salinas-Navarro
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D051379:Mice; D009409:Nerve Crush; D009798:Ocular Hypertension / Q000378:metabolism / Q000473:pathology; D020221:Optic Nerve Injuries / Q000378:metabolism / Q000473:pathology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB