Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice

Niesman, Ingrid R.; Schilling, Jan M.; Shapiro, Lee A.; Kellerhals, Sarah E; Bonds, Jacqueline A.; Kleschevnikov, Alexander M.; Cui, Weihua; Voong, April; Krajewski, Stan; Ali, Sameh S.; Roth, David M.; Patel, Hemal H.; Patel, Piyush M.; Head, Brian P.

doi:10.1186/1742-2094-11-39

Cited by 85 publications

(77 citation statements)

References 66 publications

(81 reference statements)

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“…Mice were anesthetized and prepared for sugery with a protocol modified from a previously described study (35). Hippocampal-targeted injections were controlled using Injectomate software (Neurostar – Berlin, Germany).…”

Section: Methodsmentioning

confidence: 99%

Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice

Mandyam

Schilling

Cui

et al. 2017

Biological Psychiatry

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Background Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering pro-growth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown. Methods Here we assessed the impact of neuron-targeted overexpression of a MLR scaffold protein, caveolin-1 (via a synapsin promoter; SynCav1), in the hippocampus in vivo in adult (6-months-old) and aged (20-month-old) mice on biochemical, morphologic and behavioral changes. Results SynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B (TrkB) receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal CA1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function. Conclusions Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.

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Section: Methodsmentioning

confidence: 99%

Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice

Mandyam

Schilling

Cui

et al. 2017

Biological Psychiatry

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“…Moreover, NOX inhibition in TBI models was found to reduce inflammatory injury as well (Cooney et al, 2013). Other models have also demonstrated increases in NOX activity post injury (Lu et al, 2014; Niesman et al, 2014). In TBI models, increased gp91- phox (NOX2) was also observed and mice deficient for NOX2 genes were found to have less ROS and oxidative damage, inflammation and secondary damage at the site of injury (Dohi et al, 2010).…”

Section: Nox In Diseasementioning

confidence: 97%

“…In TBI models, increased gp91- phox (NOX2) was also observed and mice deficient for NOX2 genes were found to have less ROS and oxidative damage, inflammation and secondary damage at the site of injury (Dohi et al, 2010). Moreover, post injury, the brain exhibited NMDA excitotoxicity, which may cause further NOX activation and damage (Niesman et al, 2014). As TBI derives from direct injury and the resulting neuroinflammation responses that occur, the oxidative damage done is likely due to direct ROS damage from NOX rather than through signaling pathways.…”

Section: Nox In Diseasementioning

confidence: 99%

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Rastogi

et al. 2017

Front. Cell. Neurosci.

179

167

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Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body’s antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX’s deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

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“…In astrocytes, CAV1 contributes to Aβ-induced cellular processes, including cholesterol efflux (Parat and Riggins, 2012). Additionally, Cav1 knockout mice have significantly higher rates of microgliosis and astrogliosis and more rapid onset of neurodegenerative processes (Head et al, 2010; Niesman et al, 2014). …”

Section: Pathway Analysis and Functional Annotationmentioning

confidence: 99%

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Danford

Verkuil

Choi

et al. 2017

Progress in Retinal and Eye Research

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Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the “POAGome.” We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

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Traumatic brain injury enhances neuroinflammation and lesion volume in caveolin deficient mice

Cited by 85 publications

References 66 publications

Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice

Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

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