Publications by authors named "Britta Schürmann"

15 Publications

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A novel role for the late-onset Alzheimer's disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling.

Mol Psychiatry 2020 09 9;25(9):2000-2016. Epub 2019 Apr 9.

Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Postsynaptic trafficking plays a key role in regulating synapse structure and function. While spiny excitatory synapses can be stable throughout adult life, their morphology and function is impaired in Alzheimer's disease (AD). However, little is known about how AD risk genes impact synaptic function. Here we used structured superresolution illumination microscopy (SIM) to study the late-onset Alzheimer's disease (LOAD) risk factor BIN1, and show that this protein is abundant in postsynaptic compartments, including spines. While postsynaptic Bin1 shows colocalization with clathrin, a major endocytic protein, it also colocalizes with the small GTPases Rab11 and Arf6, components of the exocytic pathway. Bin1 participates in protein complexes with Arf6 and GluA1, and manipulations of Bin1 lead to changes in spine morphology, AMPA receptor surface expression and trafficking, and AMPA receptor-mediated synaptic transmission. Our data provide new insights into the mesoscale architecture of postsynaptic trafficking compartments and their regulation by a major LOAD risk factor.
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http://dx.doi.org/10.1038/s41380-019-0407-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785379PMC
September 2020

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub.

Proc Natl Acad Sci U S A 2016 07 11;113(30):8520-5. Epub 2016 Jul 11.

Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein-protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.
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http://dx.doi.org/10.1073/pnas.1607014113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968749PMC
July 2016

Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons.

Proc Natl Acad Sci U S A 2015 May 27;112(19):6176-81. Epub 2015 Apr 27.

Departments of Physiology and Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.
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http://dx.doi.org/10.1073/pnas.1423205112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434727PMC
May 2015

Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses.

Neuron 2014 Oct 22;84(2):399-415. Epub 2014 Oct 22.

Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA. Electronic address:

Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-G, have been associated with bipolar disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules.
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http://dx.doi.org/10.1016/j.neuron.2014.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223651PMC
October 2014

Dynorphins regulate fear memory: from mice to men.

J Neurosci 2012 Jul;32(27):9335-43

Institute of Molecular Psychiatry, University of Bonn, 53125 Bonn, Germany.

Reexposure to trauma reminders is an integral element of trauma-focused cognitive behavioral therapy (Roberts et al., 2009), but little is known about the physiological processes underlying the therapeutic progress. While it is well established that amygdala, prefrontal cortex and hippocampus are key brain structures in fear memory processing (McGaugh, 2004; Herry et al., 2008; Likhtik et al., 2008), it is not well known which neurotransmitters or neuromodulators are involved. Here with a translational approach we investigated the role of dynorphins in the formation and extinction of fear memories in mice and in humans. Mice lacking dynorphin showed an enhanced cue-dependent fear conditioning, as well as delayed extinction in contextual conditioning/extinction paradigms. The pharmacological blockade of κ-opioid receptors before the extinction trials but not before or after the conditioning produced a similar effect. Analysis of neuronal activity, using the immediate early gene c-fos, demonstrated a reduced neuronal activity in key limbic structures during extinction in the absence of dynorphin. Translating these findings into the human domain, fear conditioning and extinction, coupled with functional MRI was then performed in volunteers preselected for a functionally relevant polymorphism in the dynorphin gene. Human volunteers bearing the (T) allele of PDYN (prodynorphin) at rs1997794 showed reduced fear extinction and a significantly diminished functional connectivity between amygdala and ventromedial prefrontal cortex. Our findings establish a role of dynorphin κ-opioid receptor signaling in fear extinction.
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http://dx.doi.org/10.1523/JNEUROSCI.1034-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622224PMC
July 2012

An fMRI study on the acute effects of exercise on pain processing in trained athletes.

Pain 2012 Aug 16;153(8):1702-1714. Epub 2012 Jun 16.

Functional Neuroimaging Group, Department of Radiology, University of Bonn, Germany Department of Psychiatry, University of Bonn, Germany Institute of Molecular Psychiatry, University of Bonn, Germany Institute of Forensic Medicine, University of Bonn, Germany Department of Radiology, University of Bonn, Germany.

Endurance exercise is known to promote sustained antinociceptive effects, and there is evidence that the reduction of pain perception mediated by exercise is driven by central opioidergic neurotransmission. To directly investigate the involved brain areas and the underlying neural mechanisms in humans, thermal heat-pain challenges were applied to 20 athletes during 4 separate functional magnetic resonance imaging (fMRI) scans, i.e., before and after 2 hours of running (exercise condition) and walking (control condition), respectively. Imaging revealed a reproducible pattern of distributed pain-related activation in all 4 conditions, including the mesial and lateral pain systems, and the periaqueductal gray (PAG) as a key region of the descending antinociceptive pathway. At the behavioral level, running as compared with walking decreased affective pain ratings. The influence of exercise on pain-related activation was reflected in a significant time × treatment interaction in the PAG, along with similar trends in the pregenual anterior cingulate cortex and the middle insular cortex, where pain-induced activation levels were elevated after walking, but decreased or unchanged after running. Our findings indicate that enhanced reactive recruitment of endogenous antinociceptive mechanisms after aversive repeated pain exposure is attenuated by exercise. The fact that running, but not walking, reproducibly elevated β-endorphin levels in plasma indicates involvement of the opioidergic system in exercise. This may argue for an elevated opioidergic tone in the brain of athletes, mediating antinociceptive mechanisms. Our findings provide the first evidence using functional imaging to support the role of endurance exercise in pain modulation.
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http://dx.doi.org/10.1016/j.pain.2012.05.008DOI Listing
August 2012

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells.

Proc Natl Acad Sci U S A 2012 Mar 21;109(10):3897-902. Epub 2012 Feb 21.

Institute of Molecular Psychiatry, University of Bonn, 53127 Bonn, Germany.

Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4(-/-) mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4(-/-) mice, indicating that CCR4(+) DCs are cellular mediators of EAE development. Mechanistically, CCR4(-/-) DCs were less efficient in GM-CSF and IL-23 production and also T(H)-17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4(-/-) mice, whereas intracerebral inoculation using IL-23(-/-) DCs or GM-CSF(-/-) DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.
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http://dx.doi.org/10.1073/pnas.1114153109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309768PMC
March 2012

Genome-wide association study of vascular dementia.

Stroke 2012 Feb 23;43(2):315-9. Epub 2011 Nov 23.

Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Background And Purpose: Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia.

Methods: We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples.

Results: In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3 ± 3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3-5.8, per copy of the minor allele; P=1.3 × 10(-8)). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024).

Conclusions: Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.
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http://dx.doi.org/10.1161/STROKEAHA.111.628768DOI Listing
February 2012

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

J Alzheimers Dis 2012 ;28(2):377-87

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
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http://dx.doi.org/10.3233/JAD-2011-110824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118466PMC
May 2012

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Nat Genet 2011 May 3;43(5):429-35. Epub 2011 Apr 3.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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http://dx.doi.org/10.1038/ng.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084173PMC
May 2011

Association of the Alzheimer's disease clusterin risk allele with plasma clusterin concentration.

J Alzheimers Dis 2011 ;25(3):421-4

Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.

A variant within the clusterin gene has been recently associated with increased risk for Alzheimer's disease (AD) in genome wide association studies. Here we tested the association of the respective single nucleotide polymorphisms (rs11136000) with plasma concentration of clusterin in 67 AD subjects and 191 cognitively unimpaired elderly individuals. We observed an association of the rs11136000 AD-risk variant with low clusterin plasma levels in an allele-dose dependent manner in the healthy individuals (p = 0.011). This effect was numerically also present in the AD patients. We conclude that the rs11136000 AD-risk variant is associated with low clusterin plasma levels.
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http://dx.doi.org/10.3233/JAD-2011-110251DOI Listing
November 2011

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

PLoS One 2010 Nov 15;5(11):e13950. Epub 2010 Nov 15.

Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff, United Kingdom.

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.

Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.

Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013950PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981526PMC
November 2010

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

Nat Genet 2009 Oct 6;41(10):1088-93. Epub 2009 Sep 6.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).
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http://dx.doi.org/10.1038/ng.440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845877PMC
October 2009

The opioid peptides enkephalin and beta-endorphin in alcohol dependence.

Biol Psychiatry 2008 Dec 27;64(11):989-97. Epub 2008 Jun 27.

Institute of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.

Background: Experimental evidence indicates that the endogenous opioid system influences stress responses as well as reinforces effects of addictive drugs. Because stress is an important factor contributing to drug dependence and relapse, we have now studied ethanol preference in enkephalin- and beta-endorphin-deficient mice under baseline conditions and after stress exposure.

Methods: In the present study we used a two-bottle choice paradigm to study ethanol consumption and stress-induced ethanol preference. To examine alcohol withdrawal symptoms the forced drinking procedure was employed. We performed an association analysis in two case-control samples of alcohol addicts to determine whether these opioid peptides also contribute to ethanol dependence in humans.

Results: Ethanol consumption was significantly reduced in the absence of beta-endorphins, particularly in female knockout animals. Stress exposure results in an increased ethanol consumption in wild-type mice but did not influence ethanol-drinking in beta-endorphin knockouts. Enkephalin-deficient mice showed no difference from wild-type mice in baseline ethanol preference but also showed no stress-induced elevation of ethanol consumption. Interestingly, we found a two-marker haplotype in the POMC gene that was associated with alcohol dependence in females in both cohorts.

Conclusions: Together these results indicate a contribution of beta-endorphin to ethanol consumption and dependence.
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http://dx.doi.org/10.1016/j.biopsych.2008.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646839PMC
December 2008

The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice.

J Neurosci 2005 Aug;25(34):7805-12

Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany.

Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Because accompanying inflammation may interact with and promote neurodegeneration, anti-inflammatory treatment strategies are being evaluated. Because peroxisome proliferator-activated receptor gamma (PPARgamma) agonists act as potent anti-inflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPARgamma agonist pioglitazone (Pio). Pio-treated transgenic mice revealed improved muscle strength and body weight, exhibited a delayed disease onset, and survived significantly longer than nontreated SOD1-G93A mice. Quantification of motor neurons of the spinal cord at day 90 revealed complete neuroprotection by Pio, whereas nontreated SOD1-G93A mice had lost 30% of motor neurons. This was paralleled by preservation of the median fiber diameter of the quadriceps muscle, indicating not only morphological but also functional protection of motor neurons by Pio. Activated microglia were significantly reduced at sites of neurodegeneration in Pio-treated SOD1-G93A mice, as were the protein levels of cyclooxygenase 2 and inducible nitric oxide synthase. Interestingly, mRNA levels of the suppressor of cytokine signaling 1 and 3 genes were increased by Pio, whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected.
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http://dx.doi.org/10.1523/JNEUROSCI.2038-05.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725264PMC
August 2005