| 1. |
- Darreh-Shori, Taher, et al.
(författare)
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Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
- 2013
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:11, s. 2465-2481
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Tidskriftsartikel (refereegranskat)abstract
- Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.
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| 2. |
- Lindblom, Rickard P F, et al.
(författare)
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Even small aneurysms can bleed : a ruptured small idiopathic aneurysm of the internal thoracic artery
- 2013
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Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press (OUP). - 1569-9293 .- 1569-9285. ; 17:3, s. 583-585
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Tidskriftsartikel (refereegranskat)abstract
- Internal thoracic artery (ITA) aneurysms are rare, but a rupture is potentially fatal. Most cases of ITA aneurysms are iatrogenic, caused by, for instance, previous sternotomy or pacemaker implantation. Other known aetiologies are vasculopathies, either of inflammatory origin or as part of connective tissue disorders like Marfan's syndrome, Ehler-Dahnlos syndrome or neurofibromatosis Type 1. Idiopathic ITA aneurysms are exceedingly scarce. The present case illustrates an unusual scenario, which posed diagnostic challenges, where spontaneous rupture of an idiopathic or possibly very late post-traumatic aneurysm of the left ITA led to a life-threatening bleeding, successfully treated by endovascular coiling with standby preparation for conversion to open surgery. This case demonstrates the importance of the careful interpretation of radiological findings and the significance of multidisciplinary collaboration between radiologist and clinician.
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| 3. |
- Lindblom, Rickard P F, et al.
(författare)
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Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.
- 2013
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection.METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains.RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury.CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.
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| 4. |
- Lindblom, Rickard P F
(författare)
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Impact of genetic variability on early immune reactions following nerve injury
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Injury to the central nervous system (CNS) is frequently associated with significant morbidity, in worst case mortality. This in turn leads to considerable disease burden for the individual and also for society. The spectrum of conditions that cause damage to the CNS is wide and highly diverse, ranging from acute trauma to degenerative diseases that progress over decades. But in spite of the heterogeneity, there exist common aspects. For instance, there is often interplay between the immune and nervous systems in one stage or another of disease. Also, the genetic background of the individual influences both susceptibility to and severity of the disease. This thesis focuses on the early immune reactions that occur after CNS injury in rodents, based on the hypothesis that early immune reactions affect important downstream events, not least nerve cell death. In study I a large rat experimental cross F2(DAxPVG) was created from the inbred strains DA and PVG. The global transcriptome in the spinal cord was screened using microarrays five days after ventral root avulsion (VRA), a reproducible nerve injury model. In parallel, whole genome mapping was performed. The expression and genetic data was co-analyzed to identify gene regions regulating components of the complement system, in turn associated with loss of synapses. Lastly, we identified a link between the cholinergic and complement systems, which was confirmed in vitro. In study II, data from the F2(DAxPVG) cross was used to analyze regulation of complement receptors following injury. We found a strong cis-regulatory influence acting on the expression of complement receptor 2 (CR2), a receptor mostly associated with B cell functions, but with unknown role in the adult CNS. CR2 was up regulated on astrocytes and protected from injury induced synapse loss in rodents. Levels of CR2 were increased in the cerebrospinal fluid (CSF) of rats following injury, but also in the CSF of patients with multiple sclerosis as compared to controls, implicating a possible role for CR2 also in context of human disease. Traumatic brain injury (TBI) is one of the leading causes of death in the young population. Secondary events following initial injury contribute to the damage, but are not fully understood. In study III TBI was performed on DA and PVG rats and the ensuing injury processes analyzed at both the molecular and cellular levels using microarrays and flow cytometry. Large strain differences in complement activation and the size and composition of multiple immune cell populations were found. Complement was also found to label axons of injured neurons and the degree of complement expression correlated with the levels of neurofilament-light in CSF, a marker of axonal injury. C-type lectins (CLECs) are a group of immune molecules structurally similar to members of the complement family. Study I demonstrated several loci co-regulating the expression of complement and CLEC transcripts, thus providing a link between the two families. In study IV we examined the properties of a congenic rat strain, Aplec, which onto DA background has a very small genomic insert from PVG consisting of 7 CLEC genes. The Aplec rat displayed improved survival of motor neurons following VRA compared to DA, which in turn was associated with increased infiltration of T cells. This demonstrates that CLECs convey neuroprotection after nerve root injury, potentially through T cell pathways. These results provide insights into the molecular pathways regulating inflammation after mechanical nerve injuries, in turn of relevance for nerve injury-induced synaptic remodeling and neurodegeneration.
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| 5. |
- Vijayaraghavan, Swetha, et al.
(författare)
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Regulated Extracellular Choline Acetyltransferase Activity : The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.
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