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Neuroscience

  • 443 Articles
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Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression
Jean-Eric Ghia, … , Patricia Blennerhassett, Stephen M. Collins
Jean-Eric Ghia, … , Patricia Blennerhassett, Stephen M. Collins
Published May 1, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI32849.
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Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression

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Abstract

Clinical and experimental evidence indicates that intestinal inflammatory conditions can be exacerbated by behavioral conditions such as depression. The recent demonstration of a tonic counterinflammatory influence mediated by the vagus nerve in experimental colitis provides a potential link between behavior and gut inflammation. Here we show that experimental conditions that induced depressive-like behaviors in mice increased susceptibility to intestinal inflammation by interfering with the tonic vagal inhibition of proinflammatory macrophages and that tricyclic antidepressants restored vagal function and reduced intestinal inflammation. These results show that reserpine-induced monoamine depletion and maternal separation, 2 models for depression, produced a vulnerability to colitis by a mechanism involving parasympathetic transmission and the presence of gut macrophages. The tricyclic antidepressant desmethylimipramine protected against this vulnerability by a vagal-dependent mechanism. Together these results illustrate the critical role of the vagus in both the vulnerability to inflammation induced by depressive-like conditions and the protection afforded by tricyclic antidepressants and rationalize a clinical evaluation of both parasympathomimetics and tricyclic antidepressants in treatment of inflammatory bowel disease.

Authors

Jean-Eric Ghia, Patricia Blennerhassett, Stephen M. Collins

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Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy
Jormay Lim, … , Virginia M.-Y. Lee, Kun Ping Lu
Jormay Lim, … , Virginia M.-Y. Lee, Kun Ping Lu
Published April 22, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI34308.
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Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy

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Abstract

Tau pathology is a hallmark of many neurodegenerative diseases including Alzheimer disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Genetic tau mutations can cause FTDP-17, and mice overexpressing tau mutants such as P301L tau are used as AD models. However, since no tau mutations are found in AD, it remains unclear how appropriate tau mutant mice are as an AD model. The prolyl isomerase Pin1 binds and isomerizes tau and has been implicated in protecting against neurodegeneration, but whether such Pin1 regulation is affected by tau mutations is unknown. Consistent with earlier findings that Pin1 KO induces tauopathy, here we demonstrate that Pin1 knockdown or KO increased WT tau protein stability in vitro and in mice and that Pin1 overexpression suppressed the tauopathy phenotype in WT tau transgenic mice. Unexpectedly, Pin1 knockdown or KO decreased P301L tau protein stability and abolished its robust tauopathy phenotype in mice. In contrast, Pin1 overexpression exacerbated the tauopathy phenotype in P301L tau mice. Thus, Pin1 has opposite effects on the tauopathy phenotype depending on whether the tau is WT or a P301L mutant, indicating the need for disease-specific therapies for tauopathies.

Authors

Jormay Lim, Martin Balastik, Tae Ho Lee, Kazuhiro Nakamura, Yih-Cherng Liou, Anyang Sun, Greg Finn, Lucia Pastorino, Virginia M.-Y. Lee, Kun Ping Lu

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Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis
Alexandre S. Basso, … , Michael Gozin, Howard L. Weiner
Alexandre S. Basso, … , Michael Gozin, Howard L. Weiner
Published March 13, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI33464.
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Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis

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Abstract

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75–treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75–treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.

Authors

Alexandre S. Basso, Dan Frenkel, Francisco J. Quintana, Frederico A. Costa-Pinto, Sanja Petrovic-Stojkovic, Lindsay Puckett, Alon Monsonego, Amnon Bar Shir, Yoni Engel, Michael Gozin, Howard L. Weiner

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A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI
Constantin von zur Muhlen, … , Robin P. Choudhury, Daniel C. Anthony
Constantin von zur Muhlen, … , Robin P. Choudhury, Daniel C. Anthony
Published February 14, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI33314.
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A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

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Abstract

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-α, but not IL-1β or lymphotoxin-α (LT-α), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-α injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.

Authors

Constantin von zur Muhlen, Nicola R. Sibson, Karlheinz Peter, Sandra J. Campbell, Panop Wilainam, Georges E. Grau, Christoph Bode, Robin P. Choudhury, Daniel C. Anthony

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Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain
Christian Zöllner, … , Christoph Stein, Michael Schäfer
Christian Zöllner, … , Christoph Stein, Michael Schäfer
Published February 1, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI25911.
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Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain

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Abstract

Although opioids are highly effective analgesics, they are also known to induce cellular adaptations resulting in tolerance. Experimental studies are often performed in the absence of painful tissue injury, which precludes extrapolation to the clinical situation. Here we show that rats with chronic morphine treatment do not develop signs of tolerance at peripheral μ-opioid receptors (μ-receptors) in the presence of painful CFA-induced paw inflammation. In sensory neurons of these animals, internalization of μ-receptors was significantly increased and G protein coupling of μ-receptors as well as inhibition of cAMP accumulation were preserved. Opioid receptor trafficking and signaling were reduced, and tolerance was restored when endogenous opioid peptides in inflamed tissue were removed by antibodies or by depleting opioid-producing granulocytes, monocytes, and lymphocytes with cyclophosphamide (CTX). Our data indicate that the continuous availability of endogenous opioids in inflamed tissue increases recycling and preserves signaling of μ-receptors in sensory neurons, thereby counteracting the development of peripheral opioid tolerance. These findings infer that the use of peripherally acting opioids for the prolonged treatment of inflammatory pain associated with diseases such as chronic arthritis, inflammatory neuropathy, or cancer, is not necessarily accompanied by opioid tolerance.

Authors

Christian Zöllner, Shaaban A. Mousa, Oliver Fischer, Heike L. Rittner, Mohammed Shaqura, Alexander Brack, Mehdi Shakibaei, Waltraud Binder, Florian Urban, Christoph Stein, Michael Schäfer

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Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Suzanne E. Wahrle, … , Steven M. Paul, David M. Holtzman
Suzanne E. Wahrle, … , Steven M. Paul, David M. Holtzman
Published January 17, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI33622.
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Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease

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Abstract

APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1–/– mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe–/– mice: there was significantly less amyloid β-peptide (Aβ) deposition, a redistribution of Aβ to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S–positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.

Authors

Suzanne E. Wahrle, Hong Jiang, Maia Parsadanian, Jungsu Kim, Aimin Li, Amanda Knoten, Sanjay Jain, Veronica Hirsch-Reinshagen, Cheryl L. Wellington, Kelly R. Bales, Steven M. Paul, David M. Holtzman

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The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons
Andreas Leffler, … , Peter W. Reeh, Carla Nau
Andreas Leffler, … , Peter W. Reeh, Carla Nau
Published January 2, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI32751.
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The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

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Abstract

Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na+ channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene–related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity.

Authors

Andreas Leffler, Michael J. Fischer, Dietlinde Rehner, Stephanie Kienel, Katrin Kistner, Susanne K. Sauer, Narender R. Gavva, Peter W. Reeh, Carla Nau

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Dopamine-modified α-synuclein blocks chaperone-mediated autophagy
Marta Martinez-Vicente, … , David Sulzer, Ana Maria Cuervo
Marta Martinez-Vicente, … , David Sulzer, Ana Maria Cuervo
Published January 2, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI32806.
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Dopamine-modified α-synuclein blocks chaperone-mediated autophagy

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Abstract

Altered degradation of α-synuclein (α-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that α-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of α-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic α-syn mutations are rare, α-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of α-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified α-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.

Authors

Marta Martinez-Vicente, Zsolt Talloczy, Susmita Kaushik, Ashish C. Massey, Joseph Mazzulli, Eugene V. Mosharov, Roberto Hodara, Ross Fredenburg, Du-Chu Wu, Antonia Follenzi, William Dauer, Serge Przedborski, Harry Ischiropoulos, Peter T. Lansbury, David Sulzer, Ana Maria Cuervo

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Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice
Tianfu Li, … , Roger P. Simon, Detlev Boison
Tianfu Li, … , Roger P. Simon, Detlev Boison
Published January 2, 2008
Citation Information: J Clin Invest. 2008. https://doi.org/10.1172/JCI33737.
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Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice

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Abstract

Astrogliosis is a pathological hallmark of the epileptic brain. The identification of mechanisms that link astrogliosis to neuronal dysfunction in epilepsy may provide new avenues for therapeutic intervention. Here we show that astrocyte-expressed adenosine kinase (ADK), a key negative regulator of the brain inhibitory molecule adenosine, is a potential predictor and modulator of epileptogenesis. In a mouse model of focal epileptogenesis, in which astrogliosis is restricted to the CA3 region of the hippocampus, we demonstrate that upregulation of ADK and spontaneous focal electroencephalographic seizures were both restricted to the affected CA3. Furthermore, spontaneous seizures in CA3 were mimicked in transgenic mice by overexpression of ADK in this brain region, implying that overexpression of ADK without astrogliosis is sufficient to cause seizures. Conversely, after pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis. Likewise, ADK-deficient ES cell–derived brain implants suppressed astrogliosis, upregulation of ADK, and spontaneous seizures in wild-type mice when implanted after the epileptogenesis-precipitating brain injury. Our findings suggest that astrocyte-based ADK provides a critical link between astrogliosis and neuronal dysfunction in epilepsy.

Authors

Tianfu Li, Gaoying Ren, Theresa Lusardi, Andrew Wilz, Jing Q. Lan, Takuji Iwasato, Shigeyoshi Itohara, Roger P. Simon, Detlev Boison

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Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
Jun Wang, … , Clive Rosendorff, Giulio Maria Pasinetti
Jun Wang, … , Clive Rosendorff, Giulio Maria Pasinetti
Published October 25, 2007
Citation Information: J Clin Invest. 2007. https://doi.org/10.1172/JCI31547.
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Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease

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Abstract

Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type β-amyloid protein (Aβ) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Aβ peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Aβ peptides in the brain. Most importantly, valsartan administration also attenuated the development of Aβ-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Aβ-related memory deficits in subjects with AD or in those at high risk of developing AD.

Authors

Jun Wang, Lap Ho, Linghong Chen, Zhong Zhao, Wei Zhao, Xianjuan Qian, Nelson Humala, Ilana Seror, Sadie Bartholomew, Clive Rosendorff, Giulio Maria Pasinetti

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DREAM suppression in Huntington’s disease
José Naranjo and colleagues reveal that downregulation of DREAM mediates derepression of ATF6, and this elevation of ATF6 plays an early neuroprotective role in Huntington’s disease…
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Extra-cerebellar motor symptoms in Angelman’s syndrome
Caroline Bruinsma and colleagues evaluated cerebellar involvement in Angelman’s Syndrome motor deficits…
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An epigenetic intervention for neurodegenerative diseases
Eva Benito and colleagues demonstrate that SAHA, a histone-deacetylase inhibitor, improves spatial memory and selectively regulates the neuronal epigenome in a mouse model of neurodegeneration…
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Genetic and environmental interactions in Parkinson’s disease
Alevtina Zharikov and colleagues reveal that interplay between α-synuclein and environmental toxin exposure influences parkinsonian neurodegeneration…
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TREM2 keeps myelinated axons under wraps
Pietro Poliani, Yaming Wang, and colleagues demonstrate that TREM2 deficiency reduces age-associated expansion of microglia and microglia-dependent remyelination…
Published April 20, 2015
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Synergy among Parkinson’s disease-associated genes
Durga Meka and colleagues demonstrate that crosstalk between parkin and RET maintains mitochondrial integrity and protects dopaminergic neurons…
Published March 30, 2015
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A model of periventricular leukomalacia
Tamar Licht, Talia Dor-Wollman and colleagues demonstrate that specific vulnerability of immature blood vessels surrounding ventricles predisposes to hypoxia-induced periventricular leukomalacia…
Published February 17, 2015
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