| 1. |
- Aldskogius, Håkan, et al.
(författare)
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Central neuron-glial and glial-glial interactions following axon injury
- 1998
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Ingår i: Progress in Neurobiology. - 0301-0082 .- 1873-5118. ; 55:1, s. 1-26
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Tidskriftsartikel (refereegranskat)abstract
- Axon injury rapidly activates microglial and astroglial cells close to the axotomized neurons. Following motor axon injury, astrocytes upregulate within hour(s) the gap junction protein connexin-43, and within one day glial fibrillary acidic protein (GFAP). Concomitantly, microglial cells proliferate and migrate towards the axotomized neuron perikarya. Analogous responses occur in central termination territories of peripherally injured sensory ganglion cells. The activated microglia express a number of inflammatory and immune mediators. When neuron degeneration occurs, microglia act as phagocytes. This is uncommon after peripheral nerve injury in the adult mammal, however, and the functional implications of the glial cell responses in this situation are unclear. When central axons are injured, the glial cell responses around the affected neuron perikarya appears to be minimal or absent, unless neuron degeneration occurs. Microglia proliferate, and astrocytes upregulate GFAP along central axons undergoing anterograde, Wallerian, degeneration. Although microglia develop into phagocytes, they eliminate the disintegrating myelin very slowly, presumably because they fail to release molecules which facilitate phagocytosis. During later stages of Wallerian degeneration, oligodendrocytes express clusterin, a glycoprotein implicated in several conditions of cell degeneration. A hypothetical scheme for glial cell activation following axon injury is discussed, implying the injured neurons initially interact with adjacent astrocytes. Subsequently, neighbouring resting microglia are activated. These glial reactions are amplified by paracrine and autocrine mechanisms, in which cytokines appear to be important mediators. The specific functional properties of the activated glial cells will determine their influence on neuronal survival, axon regeneration, and synaptic plasticity. The control of the induction and progression of these responses are therefore likely to be critical for the outcome of, for example, neurotrauma, brain ischemia and chronic neurodegenerative diseases.
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| 4. |
- Andrade-Talavera, Yuniesky, et al.
(författare)
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S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS
- 2022
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Ingår i: Progress in Neurobiology. - : Elsevier. - 0301-0082 .- 1873-5118. ; 219
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Tidskriftsartikel (refereegranskat)abstract
- The pro-inflammatory and highly amyloidogenic protein S100A9 is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases leading to cognitive impairment. Molecular chaperone activity of Bri2 BRICHOS has been demonstrated against a range of amyloidogenic polypeptides. Using a combination of thioflavin T fluorescence kinetic assay, atomic force microscopy and immuno electron microscopy we show here that recombinant Bri2 BRICHOS effectively inhibits S100A9 amyloid growth by capping amyloid fibrils. Using ex-vivo neuronal network electrophysiology in mouse brain slices we also show that both native S100A9 and amyloids of S100A9 disrupt cognition-relevant gamma oscillation power and rhythmicity in hippocampal area CA3 in a time- and protein conformation-dependent manner. Both effects were associated with Toll-like receptor 4 (TLR4) activation and were not observed upon TLR4 blockade. Importantly, S100A9 that had co-aggregated with Bri2 BRICHOS did not elicit degradation of gamma oscillations. Taken together, this work provides insights on the potential influence of S100A9 on cognitive dysfunction in Alzheimer's disease (AD) via gamma oscillation impairment from experimentally-induced gamma oscillations, and further highlights Bri2 BRICHOS as a chaperone against detrimental effects of amyloid self-assembly.
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| 7. |
- Bastide, Matthieu F, et al.
(författare)
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Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.
- 2015
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 132:Jul 21, s. 96-168
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Forskningsöversikt (refereegranskat)abstract
- Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.
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| 9. |
- Bäckström, Torbjörn, et al.
(författare)
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Allopregnanolone and mood disorders
- 2014
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 113, s. 88-94
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Tidskriftsartikel (refereegranskat)abstract
- Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. Conclusion: These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.(c) 2013 Elsevier Ltd. All rights reserved.
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| 11. |
- 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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| 12. |
- Dunning, Christopher, et al.
(författare)
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Can Parkinson's disease pathology be propagated from one neuron to another?
- 2012
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 97, s. 205-219
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease is the second most prevalent neurodegenerative disease, yet despite this, very little is known about the underlying cellular mechanisms. Initially it was thought to be a disease primarily involving loss of dopaminergic neurons in the substantia nigra pars compacta. Recent studies, however, have focused on observations that aggregated α-synuclein protein, the major component of Lewy bodies, is found throughout the nervous system. It is speculated that misfolded α-synuclein transfers between cells in a prion-like manner, thereby mediating the spread of the neuropathology. In this review, we discuss the staging (according to Braak) of Parkinson pathology and the concept describing the disease progression from one region of the brain to the other. We highlight how α-synuclein might be responsible for the spread of the disease. We compare the idea of a prion-like mechanism contributing to Parkinson's disease to emerging concepts that other proteins participate in similar processes in other neurodegenerative diseases. We then examine the future implications of a critical role in disease pathogenesis of α-synuclein for the classification, diagnosis and treatment of Parkinson's disease in the future.
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| 16. |
- Ghavami, Saeid, 1965-, et al.
(författare)
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Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders
- 2014
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Ingår i: Progress in Neurobiology. - Kidlington, Oxford, United Kingdom : Pergamon Press. - 0301-0082 .- 1873-5118. ; 112, s. 24-49
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Forskningsöversikt (refereegranskat)abstract
- Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.
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| 19. |
- Hailer, Nils P.
(författare)
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Immunosuppression after traumatic or ischemic CNS damage : it is neuroprotective and illuminates the role of microglial cells
- 2008
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 84:3, s. 211-233
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Forskningsöversikt (refereegranskat)abstract
- Acute traumatic and ischemic events in the central nervous system (CNS) invariably result in activation of microglial cells as local representatives of the immune system. It is still under debate whether activated microglia promote neuronal survival, or whether they exacerbate the original extent of neuronal damage. Protagonists of the view that microglial cells cause secondary damage have proposed that inhibition of microglial activation by immunosuppression is beneficial after acute CNS damage. It is the aim of this review to analyse the effects of immunosuppressants on isolated microglial cells and neurons, and to scrutinize the effects of immunosuppression in different in vivo models of acute CNS trauma or ischemia. It is found that the immunosuppressants cytosine-arabinoside, different steroids, cyclosporin A, FK506, rapamycin, mycophenolate mofetil, and minocycline all have direct inhibitory effects on microglial cells. These effects are mainly exerted by inhibiting microglial proliferation or microglial secretion of neurotoxic substances such as proinflammatory cytokines and nitric oxide. Furthermore, immunosuppression after acute CNS trauma or ischemia results in improved structure preservation and, mostly, in enhanced function. However, all investigated immunosuppressants also have direct effects on neurons, and some immunosuppressants affect other glial cells such as astrocytes. In summary, it is safe to conclude that immunosuppression after acute CNS trauma or ischemia is neuroprotective. Furthermore, circumferential evidence indicates that microglial activation after traumatic or ischemic CNS damage is not beneficial to adjacent neurons in the immediate aftermath of such acute lesions. Further experiments with more specific agents or genetic approaches that specifically inhibit microglial cells are needed in order to fully answer the question of whether microglial activation is "good or bad".
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| 20. |
- Hampel, Harald, et al.
(författare)
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Biomarkers for Alzheimer's disease therapeutic trials.
- 2011
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 579-593
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Forskningsöversikt (refereegranskat)abstract
- The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.
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| 25. |
- Kalafateli, Aimilia Lydia, 1987, et al.
(författare)
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An amylin and calcitonin receptor agonist modulates alcohol behaviors by acting on reward-related areas in the brain.
- 2021
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 200
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol causes stimulatory behavioral responses by activating reward-processing brain areas including the laterodorsal (LDTg) and ventral tegmental areas (VTA) and the nucleus accumbens (NAc). Systemic administration of the amylin and calcitonin receptor agonist salmon calcitonin (sCT) attenuates alcohol-mediated behaviors, but the brain sites involved in this process remain unknown. Firstly, to identify potential sCT sites of action in the brain, we used immunohistochemistry after systemic administration of fluorescent-labeled sCT. We then performed behavioral experiments to explore how infused sCT into the aforementioned reward-processing brain areas affects acute alcohol-induced behaviors in mice and chronic alcohol consumption in rats. We show that peripheral sCT crosses the blood brain barrier and is detected in all the brain areas studied herein. sCT infused into the LDTg attenuates alcohol-evoked dopamine release in the NAc shell in mice and reduces alcohol intake in rats. sCT into the VTA blocks alcohol-induced locomotor stimulation and dopamine release in the NAc shell in mice and decreases alcohol intake in rats. Lastly, sCT into the NAc shell prevents alcohol-induced locomotor activity in mice. Our data suggest that central sCT modulates the ability of alcohol to activate reward-processing brain regions.
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