Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target.
Animal; Animals; Astrocytes/*metabolism; Axonal Transport/*physiology; Brain-Derived Neurotrophic Factor/*metabolism; Disease Models; Glaucoma/genetics/*metabolism; Messenger/genetics/metabolism; Mice; Optic Nerve Diseases/genetics/metabolism; Rats; Retinal Ganglion Cells/*metabolism; RNA; Superior Colliculi/metabolism; Synapses/*metabolism; Visual Pathways/metabolism
Failure of anterograde transport to distal targets in the brain is a common feature of neurodegenerative diseases. We have demonstrated in rodent models of glaucoma, the most common optic neuropathy, early loss of anterograde transport along the retinal ganglion cell (RGC) projection to the superior colliculus (SC) is retinotopic and followed by a period of persistence of RGC axon terminals and synapses through unknown molecular pathways. Here we use the DBA/2J mouse model of hereditary glaucoma and an acute rat model to demonstrate that retinotopically focal transport deficits in the SC are accompanied by a spatially coincident increase in brain-derived neurotrophic factor (BDNF), especially in hypertrophic astrocytes. These neurochemical changes occur prior to loss of RGC synapses in the DBA/2J SC. In contrast to BDNF protein, levels of Bdnf mRNA decreased with transport failure, even as mRNA encoding synaptic structures remained unchanged. In situ hybridization signal for Bdnf mRNA was the strongest in SC neurons, and labeling for the immature precursor pro-BDNF was very limited. Subcellular fractionation of SC indicated that membrane-bound BDNF decreased with age in the DBA/2J, while BDNF released from vesicles remained high. These results suggest that in response to diminished axonal function, activated astrocytes in the brain may sequester mature BDNF released from target neurons to counter stressors that otherwise would challenge survival of projection synapses.
Crish S D; Dapper J D; MacNamee S E; Balaram P; Sidorova T N; Lambert W S; Calkins D J
Neuroscience
2013
2013-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuroscience.2012.10.069" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2012.10.069</a>
Alpha-lipoic Acid Antioxidant Treatment Limits Glaucoma-related Retinal Ganglion Cell Death And Dysfunction
controlled trial aladin; dba/2j mouse model; glycation end-products; in-vivo; ischemia-reperfusion; nitric-oxide; open-angle glaucoma; optic neuropathy; oxidative stress; Science & Technology - Other Topics; trabecular meshwork
Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant alpha-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma.
Inman D M; Lambert W S; Calkins D J; Horner P J
Plos One
2013
2013-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1371/journal.pone.0065389" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0065389</a>