Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma.
OBJECTIVE
In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys.


METHODS
Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus.


RESULTS
With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes.


CONCLUSIONS
Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.
Pease
M E
ME
Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
McKinnon
S J
SJ
Quigley
H A
HA
Kerrigan-Baumrind
L A
LA
Zack
D J
DJ
D000208:Acute Disease; D000818:Animals; D001345:Autoradiography; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D007429:Intraocular Pressure; D008252:Macaca fascicularis; D008297:Male; D009898:Optic Disk / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011914:Rats, Inbred BN; D020813:Receptor, trkB / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB