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Träfflista för sökning "AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper) ;pers:(Brundin Patrik)"

Sökning: AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper) > Brundin Patrik

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1.
  • Björkqvist, Maria, et al. (författare)
  • A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
  • 2008
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
  • 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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2.
  • Grey, Marie, et al. (författare)
  • Acceleration of α-synuclein aggregation by exosomes
  • 2015
  • Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 290:5, s. 2969-2982
  • Tidskriftsartikel (refereegranskat)abstract
    • Exosomes are small vesicles released from cells into extra-cellular space. We have isolated exosomes from neuroblastoma cells and investigated their influence on the aggregation of α-synuclein, a protein associated with Parkinson disease pathology. Using cryo-transmission electron microscopy of exosomes we found spherical unilamellar vesicles with a significant protein content, and Western blot analysis revealed that they contain, as expected, the proteins flotillin-1 and alix. Using thioflavin T fluorescence to monitor aggregation kinetics, we found that exosomes catalyze the process in a similar manner as low concentration of preformed α-synuclein fibrils. The exosomes reduce the lag time indicating that they provide catalytic environments for nucleation. The catalytic effect of exosomes derived from naive cells and cells that over-express α-synuclein do not differ. Vesicles prepared from extracted exosome lipids accelerate aggregation, suggesting that the lipids in exosomes are sufficient for the catalytic effect to arise. Using mass spectrometry we found several phospholipid classes in the exosomes, including phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol and the gangliosides GM2 and GM3. Within each class, several species with different acyl chains were identified. We then prepared vesicles from corresponding pure lipids or defined mixtures, most of which were found to retard α-synuclein aggregation. As a striking exception, vesicles containing ganglioside lipids GM1 or GM3 accelerate the process. Understanding how α-synuclein interacts with biological membranes to promote neurological disease might lead to the identification of novel therapeutic targets.
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4.
  • Hansson, Oskar, et al. (författare)
  • Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length
  • 2001
  • Ingår i: Journal of Neurochemistry. - Lund Univ, Sect Neuronal Survival, Wallenberg Neurosci Ctr, Dept Physiol Sci, S-22184 Lund, Sweden. State Univ Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil. Univ Uppsala, Dept Neurosci, Uppsala, Sweden. GKT, Sch Med, London, England. : BLACKWELL SCIENCE LTD. - 0022-3042 .- 1471-4159. ; 78:4, s. 694-703
  • Tidskriftsartikel (refereegranskat)abstract
    • Transgenic, Huntington's disease (HD) mice, expressing exon I of the HD gene with an expanded CAG repeat, are totally resistant to striatal, lesion induced by excessive NMDA receptor activation. We now show that striatal lesions induced by the mitochondrial toxin malonate are reduced by 70-80% in transgenic HD mice compared with wild-type littermate controls. This occurred in 6- and 12-week-old HID mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HID mice with 115 CAG repeats (line R6/1). Therefore, we show for the first time that the resistance to neurotoxin in transgenic HD mice is dependent on both the CAG repeat length and the age of the mice. Importantly, most HD patients develop symptoms in adulthood and exhibit an inverse relationship between GAG repeat length and age of onset. Transgenic mice expressing a normal CAG repeat (18 CAG) were not resistant to malonate. Although endogenous glutamate release has been implicated in malonate-induced cell death, glutamate release from striatal synaptosomes was not decreased in HID mice. Malonate-induced striatal cell death was reduced by 50-60% in wild-type mice when they were treated with either the NMDA receptor antagonist MK-801 or the caspase inhibitor zVAD-fmk. These two compounds did not reduce lesion size in transgenic R6/1 mice. This might suggest that NMDA receptor- and caspase-mediated cell death pathways are inhibited and that the limited malonate-induced cell death still occurring in HID mice is independent of these pathways. There were no changes in striatal levels of the two anti cell death proteins Bcl-X-L and X-linked Inhibitor of apoptosis protein (XIAP), before or after the lesion in transgenic HD mice. We propose that mutant huntingtin causes a sublethal grade of metabolic stress which is CAG repeat length-dependent and results in up-regulation over time of cellular defense mechanisms against impaired energy metabolism and excitotoxicity.
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5.
  • Paul-Visse, Gesine, et al. (författare)
  • The adult human brain harbors multipotent perivascular mesenchymal stem cells.
  • 2012
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.
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6.
  • Schierle, Gabriele, et al. (författare)
  • Caspase inhibition reduces apoptosis and increases survival of nigral transplants
  • 1999
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 5:1, s. 97-100
  • Tidskriftsartikel (refereegranskat)abstract
    • Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.
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7.
  • Burguillos Garcia, Miguel, et al. (författare)
  • Caspase signalling controls microglia activation and neurotoxicity.
  • 2011
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 472, s. 214-319
  • Tidskriftsartikel (refereegranskat)abstract
    • Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
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8.
  • Brundin, Patrik, et al. (författare)
  • The neurobiology of cell transplantation in Parkinson's disease
  • 2001
  • Ingår i: Clinical Neuroscience Research. - 1873-779X. ; 1:6, s. 507-520
  • Tidskriftsartikel (refereegranskat)abstract
    • Over the past decade, neural grafting has emerged as a new treatment option for Parkinson's disease. When performed successfully, grafts of human embryonic neural tissue can give rise to major symptomatic relief in patients, However, a recent report on a double-blind placebo control study, which received worldwide attention, described less pronounced beneficial effects of the grafts, and found them to be significant only in patients younger than 60 years of age. Moreover, a subgroup of patients developed disabling dyskinesias as a result of the surgery. These findings, and great logistical problems in coordinating the harvesting of sufficient amounts of suitable human embryonic donor tissue with the transplantation surgery, have led the scientific community to question whether cell transplantation really has a future as a therapy for Parkinson's disease. In this review, we argue that the future of neural transplantation for Parkinson's disease is still bright. We relate clinical findings to observations made in experimental animals grafted with embryonic neural tissue and seek explanations for the variability in outcome seen in the clinical trials. We also briefly discuss alternative sources of donor tissue that may be applied in future clinical trials, and mention what features of cells may be crucial for them to be suitable as donor tissue for transplantation in Parkinson's disease.
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9.
  • Grabowski, Martin, et al. (författare)
  • Functional integration of cortical grafts placed in brain infarcts of rats
  • 1993
  • Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 34:3, s. 362-368
  • Tidskriftsartikel (refereegranskat)abstract
    • Five to 6 days after a right middle cerebral artery occlusion, a cell suspension of fetal neocortex was grafted into the infarcted area of adult spontaneously hypertensive rats. Three to 17 months later, functional integration of the grafts into the afferent somatosensory pathway was tested using the 2-[14C]deoxyglucose method for estimation of glucose utilization. Grafted rats (n = 8) and control rats (n = 5) with no arterial occlusion were stimulated in the left vibrissal region resulting in an increased glucose utilization in the left trigeminal sensory nucleus and the right ventroposterior nucleus of the thalamus, whereas the same regions in a group (n = 5) of nonstimulated grafted rats were not activated. Glucose uptake in the right somatosensory cortex of control rats was 96 +/- 5 (mean +/- SEM) mumol/100 gm/min. Neocortical grafts consumed less glucose than cortex in control rats but the vibrissae-stimulated group displayed a 110% higher value than the nonstimulated grafted group (32 +/- 5 vs 15 +/- 2, p < 0.05). We conclude that graft glucose metabolism is increased following stimulation of the host somatosensory pathway, which demonstrates that transplanted neurons can be functionally integrated with neural circuitries of the host after an ischemic insult.
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10.
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