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| 2. |
- Björkqvist, Maria
(författare)
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Immunomodulation - a disease-modifying avenue for treatment of Huntington's disease?
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 137:5, s. 670-672
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Tidskriftsartikel (refereegranskat)abstract
- This Editorial highlights a study published in the current issue of Journal of Neurochemistry by Dobson et al. (), investigating whether the immunomodulatory agent, laquinimod exerts an immunomodulatory effect on isolated Huntington´s disease monocytes. In Huntington´s disease (HD) a central immune activation is mirrored in the periphery by a low-grade immune response and monocytes isolated from HD gene carriers have been shown pathologically hyperreactive in response to stimulation. This hyperreactive immune system has become recognized as an important feature of HD pathogenesis and the employment of a strategy to affect this hyperreactivity could be a potential disease-modifying avenue in HD. Read the highlighted article 'Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells' on doi: 10.1111/jnc.13553.
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| 3. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Fluid-based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 151:4, s. 417-434
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.
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| 4. |
- Carlred, Louise M, 1985, et al.
(författare)
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Probing Amyloid-β Pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI Imaging Mass Spectrometry
- 2016
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 138:3, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by accumulation and aggregation of amyloid-β (Aβ) peptides into extracellular plaques, however the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) based imaging was used to study Aβ deposition in transgenic mouse brain tissue and to elucidate the plaque associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aβ deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser micro dissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest (ROI) revealed brain region specific differences in Aβ peptide aggregation. Moreover, other plaque associated protein species were identified including macrophage migration inhibitory factor (MIF) suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as powerful approach in neuropathology.
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| 8. |
- Cuellar-Baena, Sandra, et al.
(författare)
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Assessment of brain metabolite correlates of AAV-mediated overexpression of human alpha-synuclein in cortical neurons by in vivo(1) H-MR spectroscopy at 9.4 T.
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 137:5, s. 806-819
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild type alpha-synuclein (a-syn) overexpression. Our goal was to find out if the increased a-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human a-syn formed the experimental group, whereas green fluorescent protein (GFP) expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data was acquired at 2, 4 and 8 month time-points. Nineteen metabolites were quantified in the MR spectra using LCModel software. Based on 92 spectra, we evaluated any potential gender effect and found that Lactate levels were lower in males compared to females, while the opposite was observed for Ascorbate. Next, we assessed the effect of age and found increased levels of GABA, Tau and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lactate levels (p=0.005) were specifically lower in the a-syn group compared to the GFP and control groups. Additionally, Ascorbate levels (p=0.05) were increased in the vector-injected groups, while glucose levels remained unchanged. This study indicates that the metabolic switch between Glucose-Lactate could be detectable in-vivo and might be modulated by Ascorbate. No concomitant changes were found in markers of neuronal integrity (e.g. NAA) consistent with the fact that a-syn overexpression in cortical neurons did not result in neurodegeneration in this model. This article is protected by copyright. All rights reserved.
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| 9. |
- de Oliveira, Ramatis B., et al.
(författare)
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Crosstalk between mitochondria, calcium channels and actin cytoskeleton modulates noradrenergic activity of locus coeruleus neurons
- 2019
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Ingår i: Journal of Neurochemistry. - : WILEY. - 0022-3042 .- 1471-4159. ; 149:4, s. 471-487
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Tidskriftsartikel (refereegranskat)abstract
- Locus coeruleus (LC) is the name of a group of large sized neurons located at the brain stem, which provides the main source of noradrenaline to the central nervous system, virtually, innervating the whole brain. All noradrenergic signalling provided by this nucleus is dependent on an intrinsic pacemaker process. Our study aims to understand how noradrenergic neurons finely tune their pacemaker processes and regulate their activities. Here we present that mitochondrial perturbation in the LC from mice, inhibits spontaneous firing by a hyperpolarizing response that involves Ca2+ entry via L-type Ca2+ channels and the actin cytoskeleton. We found that pharmacological perturbation of mitochondria from LC neurons using the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced a dominant hyperpolarizing response when electrophysiological approaches were performed. Surprisingly, the CCCP-induced hyperpolarizing response was dependent on L-type Ca2+ channel-mediated Ca2+ entry, as it was inhibited by: the removal of extracellular Ca2+; the addition of Cd2+; nifedipine or nicardipine; but not by the intracellular dialysis with the Ca2+ chelator 1,2-Bis(2-Aminophenoxy)ethane-N,N,N ',N '-tetraacetic acid, the latter indicating that the response was not because of a global change in [Ca2+](c) but does not exclude action at intracellular microdomains. Further to this, the incubation of slices with cytochalasin D, an agent that depolymerises the actin cytoskeleton, inhibited the hyperpolarizing response indicating an involvement of the actin cytoskeleton. The data are consistent with the hypothesis that there is a crosstalk between mitochondria and L-type Ca2+ channels leading to modulation of noradrenergic neuronal activity mediated by the actin cytoskeleton. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at.
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| 10. |
- Do, Hai Thi, et al.
(författare)
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Nerve growth factor (NGF) and pro-NGF increase low-density lipoprotein (LDL) receptors in neuronal cells partly by different mechanisms : role of LDL in neurite outgrowth
- 2016
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Ingår i: Journal of Neurochemistry. - : WILEY. - 0022-3042 .- 1471-4159. ; 136:2, s. 306-315
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Tidskriftsartikel (refereegranskat)abstract
- Low-density lipoprotein receptors (LDLRs) mediate the uptake of lipoprotein particles into cells, as studied mainly in peripheral tissues. Here, we show that nerve growth factor (NGF) increases LDLR levels in PC6.3 cells and in cultured septal neurons from embryonic rat brain. Study of the mechanisms showed that NGF enhanced transcription of the LDLR gene, acting mainly via Tropomyosin receptor kinase A receptors. Simvastatin, a cholesterol-lowering drug, also increased the LDLR expression in PC6.3 cells. In addition, pro-NGF and pro-brain-derived neurotrophic factor, acting via the p75 neurotrophin receptor (p75NTR) also increased LDLRs. We further observed that Myosin Regulatory Light Chain-Interacting Protein/Inducible Degrader of the LDLR (Mylip/Idol) was down-regulated by pro-NGF, whereas the other LDLR regulator, proprotein convertase subtilisin kexin 9 (PCSK9) was not significantly changed. On the functional side, NGF and pro-NGF increased lipoprotein uptake by neuronal cells as shown using diacetyl-labeled LDL. The addition of serum-derived lipoprotein particles in conjunction with NGF or simvastatin enhanced neurite outgrowth. Collectively, these results show that NGF and simvastatin are able to stimulate lipoprotein uptake by neurons with a positive effect on neurite outgrowth. Increases in LDLRs and lipoprotein particles in neurons could play a functional role during brain development, in neuroregeneration and after brain injuries.
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| 11. |
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| 12. |
- Forsberg, My, et al.
(författare)
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Ionized calcium in human cerebrospinal fluid and its influence on intrinsic and synaptic excitability of hippocampal pyramidal neurons in the rat.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 149:4, s. 452-470
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Tidskriftsartikel (refereegranskat)abstract
- It is well-known that the extracellular concentration of calcium affects neuronal excitability and synaptic transmission. Less is known about the physiological concentration of extracellular calcium in the brain. In electrophysiological brain slice experiments, the artificial cerebrospinal fluid traditionally contains relatively high concentrations of calcium (2-4 mM) to support synaptic transmission and suppress neuronal excitability. Using an ion-selective electrode, we determined the fraction of ionized calcium in healthy human cerebrospinal fluid to 1.0mM of a total concentration of 1.2 mM (86%). Using patch-clamp and extracellular recordings in the CA1 region in acute slices of rat hippocampus, we then compared the effects of this physiological concentration of calcium with the commonly used 2 mM on neuronal excitability, synaptic transmission, and long-term potentiation (LTP) to examine the magnitude of changes in this range of extracellular calcium. Increasing the total extracellular calcium concentration from 1.2 to 2 mM decreased spontaneous action potential firing, induced a depolarization of the threshold, and increased the rate of both de- and repolarization of the action potential. Evoked synaptic transmission was approximately doubled, with a balanced effect between inhibition and excitation. In 1.2mM calcium high-frequency stimulation did not result in any LTP, whereas a prominent LTP was observed at 2 or 4 mM calcium. Surprisingly, this inability to induce LTP persisted during blockade of GABAergic inhibition. In conclusion, an increase from the physiological 1.2 mM to 2 mM calcium in the artificial cerebrospinal fluid has striking effects on neuronal excitability, synaptic transmission, and the induction of LTP.
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| 13. |
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| 14. |
- Heusser, Stephanie A., et al.
(författare)
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Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 138:2, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate-gated chloride channel (GluCl(cryst)) as a structurally accessible model for GABA(A) receptors. In contrast to native-like controls, GluCl(cryst) exhibits classical activation by its neurotransmitter ligand L-glutamate. The modified channel is also sensitive to allosteric modulators associated with human GABA(A) receptors, and to site-directed mutations predicted to alter channel opening.
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| 18. |
- Lebkuechner, Isabell, et al.
(författare)
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Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency
- 2015
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 135:2, s. 234-248
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4days after entorhinal cortex lesion. To determine the Notch signaling competence of individual astrocytes, we measured the mRNA levels of Notch ligands and Notch1 receptor. We found that whereas most cultured and freshly isolated astrocytes were competent to receive Notch signals, only a minority of astrocytes were competent to send Notch signals. Injury increased the fraction of astrocyte subpopulation unable to send and receive Notch signals, thus resembling primary astrocytes invitro. Astrocytes deficient of GFAP and vimentin showed decreased Notch signal sending competence and altered expression of Notch signaling pathway-related genes Dlk2, Notch1, and Sox2. Furthermore, we identified astrocyte subpopulations based on their mRNA and protein expression of nestin and HB-EGF. This study improves our understanding of astrocyte heterogeneity, and points to astrocyte cytoplasmic intermediate filaments as targets for neural cell replacement strategies.
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| 19. |
- Li, Kenan, et al.
(författare)
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Sex differences in neonatal mouse brain injury after hypoxia-ischemia and adaptaquin treatment
- 2019
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 150:6, s. 759-775
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-PHDs) are important targets against oxidative stress. We hypothesized that inhibition HIF-PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia-ischemia (HI) and then every 24 h for 3 days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72 h after HI compared to vehicle alone, and this reduction was more pronounced in males (34.8%) than in females (11.7%). The protection was also more pronounced in the cortex. The subcortical white matter injury as measured by tissue loss volume was reduced by 24.4% in the adaptaquin treatment group, and this reduction was also more pronounced in males (28.4%) than in females (18.9%). Cell death was decreased in the cortex as indicated by Fluoro-Jade labeling, but not in other brain regions with adaptaquin treatment. Furthermore, in the brain injury area, adaptaquin did not alter the number of cells positive for caspase-3 activation or translocation of apoptosis-inducing factor to the nuclei. Adaptaquin treatment increased glutathione peroxidase 4 mRNA expression in the cortex but had no impact on 3-nitrotyrosine, 8-hydroxy-2 deoxyguanosine, or malondialdehyde production. Hif1 alpha mRNA expression increased after HI, and adaptaquin treatment also stimulated Hif1 alpha mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1 alpha protein was decreased after HI, and adaptaquin treatment had no influence on HIF1 alpha expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at .
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| 20. |
- Lundgren, Jolanta L, et al.
(författare)
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ADAM10 and BACE1 are localized to synaptic vesicles.
- 2015
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:3, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic degeneration and accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain are hallmarks of Alzheimer disease. Aβ is produced by sequential cleavage of its precursor protein, APP, by the β-secretase BACE1 and γ-secretase. However, Aβ generation is precluded if APP is cleaved by the α-secretase ADAM10 instead of BACE1. We have previously shown that Aβ can be produced locally at the synapse. To study the synaptic localization of the APP processing enzymes we used western blotting to demonstrate that, compared to total brain homogenate, ADAM10 and BACE1 were greatly enriched in synaptic vesicles isolated from rat brain using controlled-pore glass chromatography, whereas Presenilin1 was the only enriched component of the γ-secretase complex. Moreover, we detected ADAM10 activity in synaptic vesicles and enrichment of the intermediate APP-C-terminal fractions (APP-CTFs). We confirmed the western blotting findings using in situ proximity ligation assay to demonstrate close proximity of ADAM10 and BACE1 with the synaptic vesicle marker synaptophysin in intact mouse primary hippocampal neurons. In contrast, only sparse co-localization of active γ-secretase and synaptophysin was detected. These results indicate that the first step of APP processing occurs in synaptic vesicles whereas the final step is more likely to take place elsewhere. This article is protected by copyright. All rights reserved.
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| 21. |
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| 22. |
- Michno, Wojciech, 1992, et al.
(författare)
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Molecular imaging mass spectrometry for probing protein dynamics in neurodegenerative disease pathology
- 2019
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 151:4, s. 488-506
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Forskningsöversikt (refereegranskat)abstract
- Recent advances in the understanding of basic pathological mechanisms in various neurological diseases depend directly on the development of novel bioanalytical technologies that allow sensitive and specific chemical imaging at high resolution in cells and tissues. Mass spectrometry-based molecular imaging (IMS) has gained increasing popularity in biomedical research for mapping the spatial distribution of molecular species in situ. The technology allows for comprehensive, untargeted delineation of in situ distribution profiles of metabolites, lipids, peptides and proteins. A major advantage of IMS over conventional histochemical techniques is its superior molecular specificity. Imaging mass spectrometry has therefore great potential for probing molecular regulations in CNS-derived tissues and cells for understanding neurodegenerative disease mechanism. The goal of this review is to familiarize the reader with the experimental workflow, instrumental developments and methodological challenges as well as to give a concise overview of the major advances and recent developments and applications of IMS-based protein and peptide profiling with particular focus on neurodegenerative diseases. This article is part of the Special Issue “Proteomics”. (Figure presented.).
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| 23. |
- Mollenhauer, Brit, et al.
(författare)
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Antibody-based methods for the measurement of α-synuclein concentration in human cerebrospinal fluid - method comparison and round robin study.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 149:1, s. 126-138
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Tidskriftsartikel (refereegranskat)abstract
- α-Synuclein is the major component of Lewy bodies and a candidate biomarker for neurodegenerative diseases in which Lewy bodies are common, including Parkinson's disease and dementia with Lewy bodies. A large body of literature suggests that these disorders are characterized by reduced concentrations of α-synuclein in cerebrospinal fluid (CSF), with overlapping concentrations compared to healthy controls and variability across studies. Several reasons can account for this variability, including technical ones, such as inter-assay and inter-laboratory variation (reproducibility). We compared four immunochemical methods for the quantification of α-synuclein concentration in 50 unique CSF samples. All methods were designed to capture most of the existing α-synuclein forms in CSF ('total' α-synuclein). Each of the four methods showed high analytical precision, excellent correlation between laboratories (R2 0.83-0.99), and good correlation with each other (R2 0.64-0.93), although the slopes of the regression lines were different between the four immunoassays. The use of common reference CSF samples decreased the differences in α-synuclein concentration between detection methods and technologies. Pilot data on an immunoprecipitation mass spectrometry (IP-MS) method isalso presented. Our results suggest that the four immunochemical methods and the IP-MS method measure similarforms of α-synuclein and that a common reference materialwould allow harmonization of results between immunoassays.
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