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Rapid Repeat Exposure to Subthreshold Trauma Causes Synergistic Axonal Damage and Functional Deficits in the Visual Pathway in a Mouse Model.
Vest V, Bernardo-Colón A, Watkins D, Kim B, Rex TS
(2019) J Neurotrauma 36: 1646-1654
MeSH Terms: Animals, Axons, Blast Injuries, Brain Injuries, Traumatic, Disease Models, Animal, Evoked Potentials, Visual, Male, Mice, Mice, Inbred C57BL, Nerve Degeneration, Optic Nerve Injuries, Visual Pathways
Show Abstract · Added April 2, 2019
We examined the effect of repeat exposure to a non-damaging insult on central nervous system axons using the optic projection as a model. The optic projection is attractive because its axons are spatially separated from the cell bodies, it is easily accessible, it is composed of long axons, and its function can be measured. We performed closed-system ocular neurotrauma in C57Bl/6 mice using bursts of 15 or 26-psi (pounds per square inch) overpressure air that caused no gross damage. We quantified the visual evoked potential (VEP) and total and degenerative axons in the optic nerve. Repeat exposure to a 15-psi air blast caused more axon damage and vision loss than a single exposure to a 26-psi air blast. However, an increased VEP latency was detected in both groups. Exposure to three 15-psi air blasts separated by 0.5 sec caused 15% axon degeneration at 2 weeks. In contrast, no axon degeneration above sham levels was detected when the interinjury interval was increased to 10 min. Exposure to 15-psi air blasts once a day for 6 consecutive days caused 3% axon degeneration. Therefore, repeat mild trauma within an interinjury interval of 1 min or less causes synergistic axon damage, whereas mild trauma repeated at a longer interinjury interval causes additive, cumulative damage. The synergistic damage may underlie the high incidence of traumatic brain injury and traumatic optic neuropathy in blast-injured service members given that explosive blasts are multiple injury events that occur in a very short time span. This study also supports the use of the VEP as a biomarker for traumatic optic neuropathy.
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12 MeSH Terms
Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline.
Hohman TJ, Tommet D, Marks S, Contreras J, Jones R, Mungas D, Alzheimer's Neuroimaging Initiative
(2017) Neurobiol Aging 58: 120-128
MeSH Terms: Aged, Aged, 80 and over, Aging, Alzheimer Disease, Biomarkers, Brain, Cognitive Aging, Cognitive Dysfunction, Executive Function, Female, Humans, Magnetic Resonance Imaging, Male, Memory, Models, Statistical, Nerve Degeneration, Neuroimaging, Organ Size
Show Abstract · Added April 10, 2018
Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
The challenge of regenerative therapies for the optic nerve in glaucoma.
Calkins DJ, Pekny M, Cooper ML, Benowitz L, Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants
(2017) Exp Eye Res 157: 28-33
MeSH Terms: Animals, Glaucoma, Humans, Nerve Degeneration, Nerve Regeneration, Neuroglia, Optic Disk, Optic Nerve Diseases, Regenerative Medicine, Retinal Ganglion Cells
Show Abstract · Added April 18, 2017
This review arose from a discussion of regenerative therapies to treat optic nerve degeneration in glaucoma at the 2015 Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration. In addition to the authors, participants included Jonathan Crowston, Andrew Huberman, Elaine Johnson, Richard Lu, Hemai Phatnami, Rebecca Sappington, and Don Zack. Glaucoma is a neurodegenerative disease of the optic nerve, and is the leading cause of irreversible blindness worldwide. The disease progresses as sensitivity to intraocular pressure (IOP) is conveyed through the optic nerve head to distal retinal ganglion cell (RGC) projections. Because the nerve and retina are components of the central nervous system (CNS), their intrinsic regenerative capacity is limited. However, recent research in regenerative therapies has resulted in multiple breakthroughs that may unlock the optic nerve's regenerative potential. Increasing levels of Schwann-cell derived trophic factors and reducing potent cell-intrinsic suppressors of regeneration have resulted in axonal regeneration even beyond the optic chiasm. Despite this success, many challenges remain. RGC axons must be able to form new connections with their appropriate targets in central brain regions and these connections must be retinotopically correct. Furthermore, for new axons penetrating the optic projection, oligodendrocyte glia must provide myelination. Additionally, reactive gliosis and inflammation that increase the regenerative capacity must be outweigh pro-apoptotic processes to create an environment within which maximal regeneration can occur.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.
Cooper ML, Crish SD, Inman DM, Horner PJ, Calkins DJ
(2016) Exp Eye Res 150: 22-33
MeSH Terms: Animals, Astrocytes, Axons, Disease Models, Animal, Glaucoma, Open-Angle, Imaging, Three-Dimensional, Mice, Mice, Inbred DBA, Nerve Degeneration, Optic Nerve, Optic Nerve Diseases, Photomicrography, Retinal Ganglion Cells, Time Factors
Show Abstract · Added February 8, 2016
Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 μm(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Neurodegeneration and Vision Loss after Mild Blunt Trauma in the C57Bl/6 and DBA/2J Mouse.
Bricker-Anthony C, Rex TS
(2015) PLoS One 10: e0131921
MeSH Terms: Animals, Blast Injuries, Blindness, Disease Models, Animal, Electroretinography, Explosions, Eye Injuries, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Microglia, Nerve Degeneration, Olfactory Mucosa, Optic Nerve, Oxidative Stress, Retina, Wounds, Nonpenetrating
Show Abstract · Added April 2, 2019
Damage to the eye from blast exposure can occur as a result of the overpressure air-wave (primary injury), flying debris (secondary injury), blunt force trauma (tertiary injury), and/or chemical/thermal burns (quaternary injury). In this study, we investigated damage in the contralateral eye after a blast directed at the ipsilateral eye in the C57Bl/6J and DBA/2J mouse. Assessments of ocular health (gross pathology, electroretinogram recordings, optokinetic tracking, optical coherence tomography and histology) were performed at 3, 7, 14 and 28 days post-trauma. Olfactory epithelium and optic nerves were also examined. Anterior pathologies were more common in the DBA/2J than in the C57Bl/6 and could be prevented with non-medicated viscous eye drops. Visual acuity decreased over time in both strains, but was more rapid and severe in the DBA/2J. Retinal cell death was present in approximately 10% of the retina at 7 and 28 days post-blast in both strains. Approximately 60% of the cell death occurred in photoreceptors. Increased oxidative stress and microglial reactivity was detected in both strains, beginning at 3 days post-injury. However, there was no sign of injury to the olfactory epithelium or optic nerve in either strain. Although our model directs an overpressure air-wave at the left eye in a restrained and otherwise protected mouse, retinal damage was detected in the contralateral eye. The lack of damage to the olfactory epithelium and optic nerve, as well as the different timing of cell death as compared to the blast-exposed eye, suggests that the injuries were due to physical contact between the contralateral eye and the housing chamber of the blast device and not propagation of the blast wave through the head. Thus we describe a model of mild blunt eye trauma.
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Role of sigma-1 receptors in neurodegenerative diseases.
Nguyen L, Lucke-Wold BP, Mookerjee SA, Cavendish JZ, Robson MJ, Scandinaro AL, Matsumoto RR
(2015) J Pharmacol Sci 127: 17-29
MeSH Terms: Animals, Humans, Models, Biological, Molecular Targeted Therapy, Nerve Degeneration, Neurodegenerative Diseases, Neuroprotective Agents, Receptors, sigma
Show Abstract · Added August 26, 2015
Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.
Copyright © 2015. Production and hosting by Elsevier B.V.
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8 MeSH Terms
Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL, Zhang W
(2014) FASEB J 28: 3579-88
MeSH Terms: Animals, Animals, Congenic, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Choroid Plexus, Endocytosis, Endothelial Cells, Female, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration, Neurons, Pregnancy, Selenium, Selenoprotein P
Show Abstract · Added September 28, 2015
Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.
© FASEB.
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21 MeSH Terms
Genetic modification of the relationship between phosphorylated tau and neurodegeneration.
Hohman TJ, Koran ME, Thornton-Wells TA, Alzheimer's Disease Neuroimaging Initiative
(2014) Alzheimers Dement 10: 637-645.e1
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Cognition Disorders, Cytokines, Female, Genome-Wide Association Study, Genotype, Humans, Lateral Ventricles, Linear Models, Magnetic Resonance Imaging, Male, Nerve Degeneration, Polymorphism, Single Nucleotide, tau Proteins
Show Abstract · Added December 10, 2014
BACKGROUND - A subset of individuals present at autopsy with the pathologic features of Alzheimer's disease having never manifest the clinical symptoms. We sought to identify genetic factors that modify the relationship between phosphorylated tau (PTau) and dilation of the lateral inferior ventricles.
METHODS - We used data from 700 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A genome-wide association study approach was used to identify PTau × single nucleotide polymorphism (SNP) interactions. Variance explained by these interactions was quantified using hierarchical linear regression.
RESULTS - Five SNP × PTau interactions passed a Bonferroni correction, one of which (rs4728029, POT1, 2.6% of variance) was consistent across ADNI-1 and ADNI-2/GO subjects. This interaction also showed a trend-level association with memory performance and levels of interleukin-6 receptor.
CONCLUSIONS - Our results suggest that rs4728029 modifies the relationship between PTau and both ventricular dilation and cognition, perhaps through an altered neuroinflammatory response.
Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Absence of transient receptor potential vanilloid-1 accelerates stress-induced axonopathy in the optic projection.
Ward NJ, Ho KW, Lambert WS, Weitlauf C, Calkins DJ
(2014) J Neurosci 34: 3161-70
MeSH Terms: Animals, Axons, Cholera Toxin, Disease Models, Animal, Functional Laterality, Intraocular Pressure, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Ocular Hypertension, Optic Nerve Diseases, Patch-Clamp Techniques, Rats, Retinal Ganglion Cells, Superior Colliculi, TRPV Cation Channels, Visual Pathways
Show Abstract · Added May 27, 2014
How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1(-/-) mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Over a 5 week period of elevated pressure induced by microbead occlusion of ocular fluid, Trpv1(-/-) accelerated both degradation of axonal transport from retinal ganglion cells to the superior colliculus and degeneration of the axons themselves in the optic nerve. Ganglion cell body loss, which is normally later in progression, occurred in nasal sectors of Trpv1(-/-) but not C57 retina. Pharmacological antagonism of TRPV1 in rats similarly accelerated ganglion cell axonopathy. Elevated ocular pressure resulted in differences in spontaneous firing rate and action potential threshold current in Trpv1(-/-) ganglion cells compared with C57. In the absence of elevated pressure, ganglion cells in the two strains had similar firing patterns. Based on these data, we propose that TRPV1 may help neurons respond to disease-relevant stressors by enhancing activity necessary for axonal signaling.
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20 MeSH Terms
α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.
Inman DM, Lambert WS, Calkins DJ, Horner PJ
(2013) PLoS One 8: e65389
MeSH Terms: Administration, Oral, Animals, Antioxidants, Axons, Cell Death, DNA Damage, Dietary Supplements, Drug Evaluation, Preclinical, Gene Expression, Glaucoma, Intraocular Pressure, Lipid Peroxidation, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Nerve Degeneration, Nitric Oxide Synthase Type II, Oxidation-Reduction, Oxidative Stress, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Retina, Retinal Ganglion Cells, Thioctic Acid, Treatment Outcome, Up-Regulation
Show Abstract · Added May 27, 2014
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 α-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.
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26 MeSH Terms