| 1. |
- Araujo, IM, et al.
(författare)
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Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus
- 2008
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 105:3, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (KA; 10 mg/kg) intraperitoneally and sacrificed 24h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labelling in the CA1 and CA3 areas of the hippocampus in the rats that received KA, as compared to saline-treated rats. Immunohistochemistry and Western blot analysis for the calpain-derived breakdown products of spectrin (SBDP) showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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| 2. |
- Araujo, I. M., et al.
(författare)
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Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons
- 2007
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 14:9, s. 1635-1646
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Tidskriftsartikel (refereegranskat)abstract
- Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl] isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+](i), and prevented a delayed increase in [Ca2+](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection.
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| 3. |
- Audoy-Remus, Julie, et al.
(författare)
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Rod-Shaped Monocytes Patrol the Brain Vasculature and Give Rise to Perivascular Macrophages under the Influence of Proinflammatory Cytokines and Angiopoietin-2
- 2008
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Ingår i: The Journal of Neuroscience. - 1529-2401. ; 28:41, s. 10187-10199
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Tidskriftsartikel (refereegranskat)abstract
- The nervous system is constantly infiltrated by blood-derived sentinels known as perivascular macrophages. Their immediate precursors have not yet been identified in situ and the mechanism that governs their recruitment is mostly unknown. Here, we provide evidence that CD68 (+)GR(-) monocytes can give rise to perivascular macrophages in mice suffering from endotoxemia. After adhesion to the endothelium, these monocytes start to crawl, adopt a rod-shaped morphology when passing through capillaries, and can manifest the ability to proliferate and form a long cytoplasmic protuberance. They are attracted in greater numbers during endotoxemia by a combination of vasoregulatory molecules, including TNF (tumor necrosis factor), interleukin-1 beta, and angiopoietin-2. After a period of several hours, some of them cross the endothelium to expand the population of perivascular macrophages. Depletion of adherent monocytes and perivascular macrophages can be achieved by injection of anti-angiopoietin-2 peptide-Fc fusion protein. This study extends our understanding of the behavior of monocytes at the blood-brain interface and provides a way to block their infiltration into the nervous tissue under inflammatory conditions.
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| 4. |
- Björkqvist, Maria, et al.
(författare)
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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
- 2008
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
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| 5. |
- Deierborg, Tomas, et al.
(författare)
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Emerging restorative treatments for Parkinson's disease.
- 2008
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 85, s. 407-432
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Tidskriftsartikel (refereegranskat)abstract
- Several exciting approaches for restorative therapy in Parkinson's disease have emerged over the past two decades. This review initially describes experimental and clinical data regarding growth factor administration. We focus on glial cell line-derived neurotrophic factor (GDNF), particularly its role in neuroprotection and in regeneration in Parkinson's disease. Thereafter, we discuss the challenges currently facing cell transplantation in Parkinson's disease and briefly consider the possibility to continue testing intrastriatal transplantation of fetal dopaminergic progenitors clinically. We also give a more detailed overview of the developmental biology of dopaminergic neurons and the potential of certain stem cells, i.e. neural and embryonic stem cells, to differentiate into dopaminergic neurons. Finally, we discuss adult neurogenesis as a potential tool for restoring lost dopamine neurons in patients suffering from Parkinson's disease.
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| 6. |
- Lane, Emma, et al.
(författare)
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Neuroinflammation in the generation of post-transplantation dyskinesia in Parkinson's disease.
- 2008
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 32, s. 220-228
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Tidskriftsartikel (refereegranskat)abstract
- The observation that neural grafts can induce dyskinesias has severely hindered the development of a transplantation therapy for Parkinson's disease (PD). We addressed the hypothesis that inflammatory responses within and around an intrastriatal graft containing dopamine neurons can trigger dyskinetic behaviors. We subjected rats to unilateral nigrostriatal lesions with 6-hydroxydopamine (6-OHDA) and treated them with L-DOPA for 21 days in order to induce abnormal involuntary movements (AIMs). Subsequently, we grafted the rats with allogeneic embryonic ventral mesencephalic tissue in the dopamine-denervated striatum. In agreement with earlier studies, the grafted rats developed dyskinesia-like AIMs in response to amphetamine. We then used two experimental approaches to induce an inflammatory response and examined if the amphetamine-induced AIMs worsened or if spontaneous AIMs developed. In one experiment, we challenged the neural graft hosts immunologically with an orthotopic skin allograft of the same genetic origin as the intracerebral neural allograft. In another experiment, we infused the pro-inflammatory cytokine interleukin 2 (IL-2) adjacent to the intrastriatal grafts using osmotic minipumps. The skin allograft induced rapid rejection of the mesencephalic allografts, leading to disappearance of the amphetamine-induced AIMs. Contrary to our hypothesis, the rejection process itself did not elicit AIMs. Likewise, the IL-2 infusion did not induce spontaneous AIMs, nor did it alter L-DOPA-induced AIMs. The IL-2 infusions did, however, elicit the predicted marked striatal inflammation, as evidenced by the presence of activated microglia and IL2Ralpha-positive cells. These results indicate that an inflammatory response in and around grafted dopaminergic neurons is not sufficient to evoke dyskinetic behaviors in experimental models of PD.
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| 7. |
- Li, Jia-Yi, et al.
(författare)
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Critical issues of clinical human embryonic stem cell therapy for brain repair.
- 2008
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Ingår i: Trends in Neurosciences. - : Elsevier BV. - 1878-108X .- 0166-2236. ; 31, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic stem cells (ESCs) provide hope as a potential regenerative therapy for neurological conditions such as Parkinson's disease and spinal cord injury. Currently, ESC-based nervous system repair faces several problems. One major hurdle is related to problems in generating large and defined populations of the desired types of neurons from human ESCs (hESCs). Moreover, survival of grafted hESC-derived cells has varied and functional recovery in recipient animals has often been disappointing. Importantly, in clinical trials, adverse effects after surgery, including tumors or vigorous immune reactions, must be avoided. Here we highlight attempts to overcome these hurdles with hESCs intended for central nervous system repair. We focus on hESC-derived dopamine-producing neurons that can be grafted in Parkinson's disease and identify critical experiments that need to be conducted before clinical trials can occur.
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| 8. |
- Li, Jia-Yi, et al.
(författare)
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Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.
- 2008
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 14, s. 501-503
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Tidskriftsartikel (refereegranskat)abstract
- Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.
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| 9. |
- Simard, Alain R, et al.
(författare)
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Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease
- 2006
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273. ; 49:4, s. 489-502
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Tidskriftsartikel (refereegranskat)abstract
- Microglia are the immune cells of the brain. Here we show a massive infiltration of highly ramified and elongated microglia within the core of amyloid plaques in transgenic mouse models of Alzheimer's disease (AD). Many of these cells originate from the bone marrow, and the beta-amyloid-40 and -42 isoforms are able to trigger this chemoattraction. These newly recruited cells also exhibit a specific immune reaction to both exogenous and endogenous beta-amyloid in the brain. Creation of a new AD transgenic mouse that expresses the thymidine kinase protein under the control of the CD11b promoter allowed us to show that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia are thus very efficient in restricting amyloid deposits. Therapeutic strategies aiming to improve their recruitment could potentially lead to a new powerful tool for the elimination of toxic senile plaques.
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| 10. |
- Smith, Ruben, et al.
(författare)
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Mutant huntingtin interacts with {beta}-tubulin and disrupts vesicular transport and insulin secretion.
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:20, s. 3942-3954
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease is a severe progressive neurodegenerative disorder caused by a CAG-expansion in the IT15 gene, which encodes huntingtin. The disease primarily affects the neostriatum and cerebral cortex and also associates with increased incidence of diabetes. Here, we show that mutant huntingtin disrupts intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin. We demonstrate that mutant huntingtin impairs glucose-stimulated insulin secretion in insulin-producing beta-cells, without altering stored levels of insulin. Using VSVG-YFP, we show that mutant huntingtin retards post-Golgi transport. Moreover, we demonstrate that the speed of insulin vesicle trafficking is reduced. Using immunoprecipitation of mutant and wild-type huntingtin in combination with mass spectrometry, we reveal an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Thus, our findings have revealed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta-cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein.
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| 11. |
- Soulet, Denis, et al.
(författare)
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Bone-marrow-derived microglia: myth or reality?
- 2008
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Ingår i: Current Opinion in Pharmacology. - : Elsevier BV. - 1471-4973 .- 1471-4892. ; 8, s. 508-518
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Tidskriftsartikel (refereegranskat)abstract
- Microglia are the immune cells of the central nervous system (CNS). They patrol the brain environment with their ramifications and they respond quickly in the presence of pathogens and brain damages. Others and we have recently reported the existence of two different types of microglia, the resident and the newly differentiated microglia that are derived from the bone marrow stem cells. Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's disease (AD). These cells are also recruited in the brain of other mouse models of brain diseases and acute injuries. They represent, therefore, a fantastic new vehicle for delivering key molecules to improve recovery, repair, and elimination of toxic proteins. However, recent studies have challenged this concept and raised concerns regarding the physiological relevance of bone-marrow-derived microglia. This review discusses both sides of the story and why the models used to follow the phenotypic fate of these cells are so crucial to reach the proper conclusion. Blood-derived progenitors have the ability to populate the CNS, especially during injuries and chronic diseases. However they do not do it in an efficient manner. Such a lack of proper recruitment may explain the delay in recovery and repair after acute damages and accumulation of toxic proteins in chronic brain diseases.
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| 12. |
- Soulet, Denis, et al.
(författare)
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Microglia
- 2008
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Ingår i: Current Biology. - : Elsevier BV. - 1879-0445 .- 0960-9822. ; 18:12, s. 506-508
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 13. |
- Soulet, Denis, et al.
(författare)
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Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system
- 2003
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 162:2, s. 257-268
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Tidskriftsartikel (refereegranskat)abstract
- The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.
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| 14. |
- Soulet, Denis, et al.
(författare)
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Role of polyamines in the control of the immune response in the brain
- 2006
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Ingår i: Polyamine cell signaling, Physiology, Pharmacology, and Cancer Research. - Totowa, NJ : Humana Press. - 9781588296252 ; , s. 279-292
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Polyamines are essential polycations involved in a large variety of biological functions, including modulation of the nucleic acid conformation, RNA export and their degradation, protein synthesis, eIF-5A posttranslational modification, signal transduction, cell growth and differentiation, and tumor progression ( 1 –bi3. These various aspects in the biology of polyamines are addressed in other sections of this book.
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| 15. |
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