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Article ; Online: Subacute and chronic proteomic and phosphoproteomic analyses of a mouse model of traumatic brain injury at two timepoints and comparison with chronic traumatic encephalopathy in human samples.

Morin, Alexander / Davis, Roderick / Darcey, Teresa / Mullan, Michael / Mouzon, Benoit / Crawford, Fiona

2022 Volume 15, Issue 1, Page(s) 62

Abstract: Repetitive mild traumatic brain injury (r-mTBI) is the most widespread type of brain trauma worldwide. The cumulative injury effect triggers long-lasting pathological and molecular changes that may increase risk of chronic neurodegenerative diseases. R- ... ...

Abstract	Repetitive mild traumatic brain injury (r-mTBI) is the most widespread type of brain trauma worldwide. The cumulative injury effect triggers long-lasting pathological and molecular changes that may increase risk of chronic neurodegenerative diseases. R-mTBI is also characterized by changes in the brain proteome, where the majority of molecules altered early post-TBI are different from those altered at more chronic phases. This differentiation may contribute to the heterogeneity of available data on potential therapeutic targets and may present an obstacle in developing effective treatments. Here, we aimed to characterize a proteome profile of r-mTBI in a mouse model at two time points - 3 and 24 weeks post last TBI, as this may be a more relevant therapeutic window for individuals suffering negative consequences of r-mTBI. We identified a great number of proteins and phosphoproteins that remain continuously dysregulated from 3 to 24 weeks. These proteins may serve as effective therapeutic targets for sub-acute and chronic stages of post r-mTBI. We also compared canonical pathway activation associated with either total proteins or phosphoproteins and revealed that they both are upregulated at 24 weeks. However, at 3 weeks post-TBI, only pathways associated with total proteins are upregulated, while pathways driven by phosphoproteins are downregulated. Finally, to assess the translatability of our data, we compared proteomic changes in our mouse model with those reported in autopsied human samples of Chronic Traumatic Encephalopathy (CTE) patients compared to controls. We observed 39 common proteins that were upregulated in both species and 24 common pathways associated with these proteins. These findings support the translational relevance of our mouse model of r-mTBI for successful identification and translation of therapeutic targets.
MeSH term(s)	Animals ; Brain Concussion/complications ; Brain Concussion/metabolism ; Brain Concussion/pathology ; Brain Injuries, Traumatic/complications ; Chronic Disease ; Chronic Traumatic Encephalopathy/complications ; Disease Models, Animal ; Humans ; Mice ; Phosphoproteins ; Proteome ; Proteomics
Chemical Substances	Phosphoproteins ; Proteome
Language	English
Publishing date	2022-07-18
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2436057-0
ISSN	1756-6606 ; 1756-6606
ISSN (online)	1756-6606
ISSN	1756-6606
DOI	10.1186/s13041-022-00945-4
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Article: Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model.

McCartan, Robyn / Gratkowski, Arissa / Browning, Mackenzie / Hahn-Townsend, Coral / Ferguson, Scott / Morin, Alexander / Bachmeier, Corbin / Pearson, Andrew / Brown, Larry / Mullan, Michael / Crawford, Fiona / Tzekov, Radouil / Mouzon, Benoit

Molecular therapy. Methods & clinical development

2023 Volume 29, Page(s) 303–318

Abstract: Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are ... ...

Abstract	Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment. One potential treatment option for TON is ST266, a cell-free biological solution containing the secretome of amnion-derived multipotent progenitor (AMP) cells. We investigated the efficacy of intranasal ST266 in a mouse model of TON induced by blunt head trauma. Injured mice treated with a 10-day regimen of ST266 showed an improvement in spatial memory and learning, a significant preservation of retinal ganglion cells, and a decrease in neuropathological markers in the optic nerve, optic tract, and dorsal lateral geniculate nucleus. ST266 treatment effectively downregulated the NLRP3 inflammasome-mediated neuroinflammation pathway after blunt trauma. Overall, treatment with ST266 was shown to improve functional and pathological outcomes in a mouse model of TON, warranting future exploration of ST266 as a cell-free therapeutic candidate for testing in all optic neuropathies.
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.04.002
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Article ; Online: A 3-month-delayed treatment with anatabine improves chronic outcomes in two different models of repetitive mild traumatic brain injury in hTau mice.

Morin, Alexander / Mouzon, Benoit / Ferguson, Scott / Paris, Daniel / Saltiel, Nicole / Browning, Mackenzie / Mullan, Mike / Crawford, Fiona

Scientific reports

2021 Volume 11, Issue 1, Page(s) 7900

Abstract: To date, an overwhelming number of preclinical studies have addressed acute treatment in mild TBI (mTBI) and repetitive mTBI (r-mTBI), whereas, in humans, there often exists a significant time gap between the injury and the first medical intervention. ... ...

Abstract	To date, an overwhelming number of preclinical studies have addressed acute treatment in mild TBI (mTBI) and repetitive mTBI (r-mTBI), whereas, in humans, there often exists a significant time gap between the injury and the first medical intervention. Our study focused on a delayed treatment with anatabine, an anti-inflammatory compound, in hTau mice using two different models of r-mTBI. The rationale for using two models of the same impact but different frequencies (5 hit mTBI over 9 days and 24 hit mTBI over 90 days) was chosen to address the heterogeneity of r-mTBI in clinical population. Following the last injury in each model, three months elapsed before the initiation of treatment. Anatabine was administered in drinking water for 3 months thereafter. Our data demonstrated that a 3-month delayed treatment with anatabine mitigated astrogliosis in both TBI paradigms but improved cognitive functions only in more-frequently-injured mice (24 hit mTBI). We also found that anatabine decreased the phosphorylation of tau protein and NFκB, which were increased after r-mTBI in both models. The ability of anatabine to suppress these mechanisms suggests that delayed treatment can be effective for clinical population of r-mTBI. The discrepancy between the two models with regard to changes in cognitive performance suggests that r-mTBI heterogeneity may influence treatment efficiency and should be considered in therapeutic development.
MeSH term(s)	Alkaloids/pharmacology ; Alkaloids/therapeutic use ; Animals ; Brain Injuries, Traumatic/drug therapy ; Cerebral Cortex/pathology ; Disease Models, Animal ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Male ; Memory/drug effects ; Mice, Transgenic ; Models, Biological ; Motor Activity/drug effects ; NF-kappa B/metabolism ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Signal Transduction/drug effects ; Treatment Outcome ; alpha7 Nicotinic Acetylcholine Receptor/agonists ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; tau Proteins/metabolism
Chemical Substances	Alkaloids ; Glial Fibrillary Acidic Protein ; NF-kappa B ; Pyridines ; alpha7 Nicotinic Acetylcholine Receptor ; tau Proteins ; anatabine (5PP654XB7D)
Language	English
Publishing date	2021-04-12
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-87161-7
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Article ; Online: Influence of traumatic brain injury on extracellular tau elimination at the blood-brain barrier.

Eisenbaum, Maxwell / Pearson, Andrew / Gratkowski, Arissa / Mouzon, Benoit / Mullan, Michael / Crawford, Fiona / Ojo, Joseph / Bachmeier, Corbin

Fluids and barriers of the CNS

2021 Volume 18, Issue 1, Page(s) 48

Abstract: Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive ... ...

Abstract	Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood-brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.
MeSH term(s)	Animals ; Blood-Brain Barrier/metabolism ; Brain Injuries, Traumatic/metabolism ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2021-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-021-00283-y
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Article ; Online: Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men.

Ojo, Joseph O / Mouzon, Benoit C / Crawford, Fiona

Experimental neurology

2016 Volume 275 Pt 3, Page(s) 389–404

Abstract: Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent ... ...

Abstract	Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field.
MeSH term(s)	Animals ; Brain Injury, Chronic/etiology ; Brain Injury, Chronic/metabolism ; Brain Injury, Chronic/pathology ; Craniocerebral Trauma/complications ; Craniocerebral Trauma/metabolism ; Craniocerebral Trauma/pathology ; Disease Models, Animal ; Humans ; Mice ; Translational Medical Research/methods ; Translational Medical Research/trends ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2015.06.003
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Article ; Online: Impact of gulf war toxic exposures after mild traumatic brain injury.

Ferguson, Scott / McCartan, Robyn / Browning, Mackenzie / Hahn-Townsend, Coral / Gratkowski, Arissa / Morin, Alexander / Abdullah, Laila / Ait-Ghezala, Ghania / Ojo, Joseph / Sullivan, Kimberly / Mullan, Michael / Crawford, Fiona / Mouzon, Benoit

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 147

Abstract: Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention ...

Abstract	Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.
MeSH term(s)	Mice ; Animals ; Gulf War ; Brain Concussion/complications ; Pyridostigmine Bromide/toxicity ; Permethrin/toxicity ; Disease Models, Animal ; Brain Injuries, Traumatic ; Pesticides ; Pharmaceutical Preparations
Chemical Substances	Pyridostigmine Bromide (KVI301NA53) ; Permethrin (509F88P9SZ) ; Pesticides ; Pharmaceutical Preparations
Language	English
Publishing date	2022-10-18
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01449-x
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Article ; Online: Unbiased Proteomic Approach Identifies Pathobiological Profiles in the Brains of Preclinical Models of Repetitive Mild Traumatic Brain Injury, Tauopathy, and Amyloidosis.

Ojo, Joseph O / Crynen, Gogce / Algamal, Moustafa / Vallabhaneni, Prashanti / Leary, Paige / Mouzon, Benoit / Reed, Jon M / Mullan, Michael / Crawford, Fiona

ASN neuro

2020 Volume 12, Page(s) 1759091420914768

MeSH term(s)	Amyloidosis/genetics ; Amyloidosis/metabolism ; Amyloidosis/pathology ; Animals ; Brain/metabolism ; Brain/pathology ; Brain Concussion/genetics ; Brain Concussion/metabolism ; Brain Concussion/pathology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Proteomics/methods ; Tauopathies/genetics ; Tauopathies/metabolism ; Tauopathies/pathology
Language	English
Publishing date	2020-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/1759091420914768
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Article ; Online: Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI.

Morin, Alexander / Mouzon, Benoit / Ferguson, Scott / Paris, Daniel / Browning, Mackenzie / Stewart, William / Mullan, Mike / Crawford, Fiona

Acta neuropathologica communications

2020 Volume 8, Issue 1, Page(s) 166

Abstract: Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in ... ...

Abstract	Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (-)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (-)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.
MeSH term(s)	Animals ; Antigens, CD/drug effects ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/drug effects ; Antigens, Differentiation, Myelomonocytic/metabolism ; Brain Concussion/metabolism ; Brain Concussion/physiopathology ; Brain Concussion/psychology ; Calcium Channel Blockers/pharmacology ; Calcium-Binding Proteins/drug effects ; Calcium-Binding Proteins/metabolism ; Glial Fibrillary Acidic Protein/drug effects ; Glial Fibrillary Acidic Protein/metabolism ; Inflammation/metabolism ; Mice ; Microfilament Proteins/drug effects ; Microfilament Proteins/metabolism ; Nifedipine/analogs & derivatives ; Nifedipine/pharmacology ; Phosphorylation ; Rotarod Performance Test ; Spatial Learning/drug effects ; Spatial Learning/physiology ; Spatial Memory/drug effects ; Spatial Memory/physiology ; Syk Kinase/antagonists & inhibitors ; Syk Kinase/drug effects ; Syk Kinase/metabolism
Chemical Substances	Aif1 protein, mouse ; Antigens, CD ; Antigens, Differentiation, Myelomonocytic ; CD68 protein, mouse ; Calcium Channel Blockers ; Calcium-Binding Proteins ; Glial Fibrillary Acidic Protein ; Microfilament Proteins ; glial fibrillary astrocytic protein, mouse ; nilvadipine (0214FUT37J) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2) ; Nifedipine (I9ZF7L6G2L)
Language	English
Publishing date	2020-10-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-020-01045-x
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Article ; Online: Inflammatory changes in optic nerve after closed-head repeated traumatic brain injury: Preliminary study.

Tzekov, Radouil / Phifer, Josie / Myers, April / Mouzon, Benoit / Crawford, Fiona

Brain injury

2016 Volume 30, Issue 12, Page(s) 1428–1435

Abstract: Background: Closed-head, repeated, mild traumatic brain injury (r-mTBI) leads to inflammatory and degenerative changes in the optic nerve of young wild type mice. This work has investigated whether similar changes may be present when the same model is ... ...

Abstract	Background: Closed-head, repeated, mild traumatic brain injury (r-mTBI) leads to inflammatory and degenerative changes in the optic nerve of young wild type mice. This work has investigated whether similar changes may be present when the same model is applied to htau mice, a transgenic mouse in which the non-mutated human tau gene is expressed on a null murine tau background. Methods: This study investigated neuropathological changes in the optic nerve in both young (15 weeks) and old (65-70 weeks) htau mice at 24 hours after r-mTBI or anaesthesia only (r-sham). Change in the level of cellularity, myelin content and astroglial reactivity were evaluated in optic nerve samples. Results: Increased cellularity and areas of demyelination were clearly detectable in the intracranial portion of the optic nerve in both young (10-15 weeks) and old (65-75) htau r-mTBI mice at 24 hours post-injury, in contrast to r-sham. Increased astroglial reactivity was also observed, together with increased tau phosphorylation. Conclusions: Localized inflammatory and degenerative response of the intracranial part of the optic nerve was detected in htau mice after r-mTBI. Further studies to clarify the cause and consequences of this phenomenon are warranted.
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article
ZDB-ID	639115-1
ISSN	1362-301X ; 0269-9052
ISSN (online)	1362-301X
ISSN	0269-9052
DOI	10.1080/02699052.2016.1219062
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Article: Converging and Differential Brain Phospholipid Dysregulation in the Pathogenesis of Repetitive Mild Traumatic Brain Injury and Alzheimer's Disease.

Ojo, Joseph O / Algamal, Moustafa / Leary, Paige / Abdullah, Laila / Mouzon, Benoit / Evans, James E / Mullan, Michael / Crawford, Fiona

Frontiers in neuroscience

2019 Volume 13, Page(s) 103

Abstract: Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer's disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an ... ...

Abstract	Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer's disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing 'pre', 'peri' and 'post' onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.
Language	English
Publishing date	2019-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.00103
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