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Strömberg, Ingrid
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Publications (10 of 39) Show all publications
Hashemian, S., O'Rourke, C., Phillips, J. B., Strömberg, I. & af Bjerkén, S. (2015). Embryonic and mature astrocytes exert different effects on neuronal growth in rat ventral mesencephalic slice cultures. SpringerPlus, 4, Article ID 558.
Open this publication in new window or tab >>Embryonic and mature astrocytes exert different effects on neuronal growth in rat ventral mesencephalic slice cultures
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2015 (English)In: SpringerPlus, E-ISSN 2193-1801, Vol. 4, 558Article in journal (Refereed) Published
Abstract [en]

One obstacle with grafting of dopamine neurons in Parkinson's disease is the insufficient ability of the transplant to reinnervate the host striatum. Another issue is the prospective interaction between the donor fetal tissue and the adult astrocytes of the host. To study nerve fiber growth and its interaction with immature/mature astrocytes, ventral mesencephalic (VM) organotypic rat tissue cultures from embryonic days (E) 12, E14, and E18 were studied up to 35 days in vitro (DIV), and co-cultures of E14 VM tissue and mature green fluorescent protein (GFP)-positive astrocytes were performed. Generally, nerve fibers grew from the tissue slice either in association with a monolayer of migrated astroglia surrounding the tissue (glial-associated), or distal to the astroglia as non-glial-associated outgrowth. The tyrosine hydroxylase (TH)-positive glial-associated nerve fiber outgrowth reached a plateau at 21 DIV in E12 and E14 cultures. In E18 cultures, TH-positive neurons displayed short processes and migrated onto the astrocytes. While the non-glial-associated nerve fiber outgrowth dominated the E14 cultures, it was found absent in E18 cultures. The GFP-positive cells in the VM and GFP-positive astrocyte co-cultures were generally located distal to the monolayer of migrated fetal astrocytes, a few GFP-positive cells were however observed within the astrocytic monolayer. In those cases TH-positive neurons migrated towards the GFP-positive cells. Both the non-glial-and glial-associated nerve fibers grew onto the GFP-positive cells. Taken together, the glial-associated growth has limited outgrowth compared to the non-glial-associated nerve fibers, while none of the outgrowth types were hampered by the mature astrocytes.

Keyword
Organotypic culture, Ventral mesencephalon, Mature astrocytes, Developmental stages
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-110567 (URN)10.1186/s40064-015-1362-3 (DOI)000361917700003 ()26435904 (PubMedID)
Available from: 2015-11-06 Created: 2015-10-23 Last updated: 2018-01-10Bibliographically approved
Kumar, A., Kopra, J., Varendi, K., Porokuokka, L. L., Panhelainen, A., Kuure, S., . . . Andressoo, J.-O. (2015). GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genetics, 11(12), Article ID e1005710.
Open this publication in new window or tab >>GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function
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2015 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 12, e1005710Article in journal (Refereed) Published
Abstract [en]

Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3'UTR targeting may constitute a useful tool in analyzing gene function.

Place, publisher, year, edition, pages
PLoS, 2015
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-116762 (URN)10.1371/journal.pgen.1005710 (DOI)000368518400039 ()26681446 (PubMedID)
Available from: 2016-02-18 Created: 2016-02-11 Last updated: 2017-11-30Bibliographically approved
Virel, A., Rehnmark, A., Orädd, G., Olmedo-Diaz, S., Faergemann, E. & Strömberg, I. (2015). Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease: phagocyte influx to the brain is promoted by bilberry-enriched diet. European Journal of Neuroscience, 42(10), 2761-2771.
Open this publication in new window or tab >>Magnetic resonance imaging as a tool to image neuroinflammation in a rat model of Parkinson's disease: phagocyte influx to the brain is promoted by bilberry-enriched diet
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 42, no 10, 2761-2771 p.Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation is a chronic event in neurodegenerative disorders. In the rat model of Parkinson's disease, including a striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA), antioxidant treatment affects the inflammatory process. Despite a heavy accumulation of microglia early after the injury, dopamine nerve fibre regeneration occurs. It remains unclear why this heavy accumulation of microglia is found early after the lesion in antioxidant-treated animals, or even more, what is the origin of these microglia. In this study magnetic resonance imaging (MRI) was used to elucidate whether the inflammatory response was generated from the blood or from activated brain microglia. Superparamagnetic iron oxide (SPIO) nanoparticles were injected intravenously prior to a striatal 6-OHDA injection to tag phagocytes in the blood. Rats were fed either with bilberry-enriched or control diet. T2*-weighted MRI scans were performed 1 week after the lesion, and hypointense areas were calculated from T2*-weighted images, to monitor the presence of SPIO particles. The results revealed that feeding the animals with bilberries significantly promoted accumulation of blood-derived immune cells. Gadolinium-enhanced MRI demonstrated no difference in leakage of the blood-brain barrier independent of diets. To conclude, bilberry-enriched diet promotes an influx of periphery-derived immune cells to the brain early after injury.

Keyword
6-OHDA, blood-brain barrier, microglia, superparamagnetic iron oxide nanoparticles
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-116111 (URN)10.1111/ejn.13044 (DOI)000368242200002 ()26273789 (PubMedID)
Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2017-11-30Bibliographically approved
Chermenina, M., Chorell, E., Pokrzywa, M., Antti, H., Almqvist, F., Strömberg, I. & Wittung-Stafshede, P. (2015). Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice. Parkinson's Disease, 1, Article ID 15024.
Open this publication in new window or tab >>Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice
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2015 (English)In: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, 15024Article in journal (Refereed) Published
Abstract [en]

The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Neurosciences
Research subject
cellforskning
Identifiers
urn:nbn:se:umu:diva-117116 (URN)10.1038/npjparkd.2015.24 (DOI)
Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2018-01-10Bibliographically approved
Hashemian, S., Marschinke, F., af Bjerkén, S. & Strömberg, I. (2014). Degradation of proteoglycans affects astrocytes and neurite formation in organotypic tissue cultures. Brain Research, 1564, 22-32.
Open this publication in new window or tab >>Degradation of proteoglycans affects astrocytes and neurite formation in organotypic tissue cultures
2014 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1564, 22-32 p.Article in journal (Refereed) Published
Abstract [en]

Chondroitin sulfate proteoglycans (CSPGs) promote nerve growth during development, and inhibit axonal growth in the adult CNS after injury. Chondroitinase ABC (ChABC) and methyl-umbelliferyl-β-d-xyloside (β-xyloside), two enzymes that degrade CSPGs, promote regeneration after injury, however, they demonstrate opposing results in tissue culture. To elucidate the effect of the two enzymes, organotypic tissue cultures, treated with ChABC or β-xyloside, were employed to monitor nerve fiber outgrowth and astrocytic migration. Rat ventral mesencephalon (VM) and spinal cord (SC) from embryonic day (E) 14 and E18 were treated early, from the plating day for 14 days in vitro, or late where treatment was initiated after being cultured for 14 days. In the early treatment of E14 VM and SC cultures, astrocytic migration and nerve fiber outgrowth were hampered using both enzymes. Early treatment of E18 cultures reduced the astrocytic migration, while nerve growth was promoted by β-xyloside, but not by ChABC. In the late treated cultures of both E14 and E18 cultures, no differences in distances that astrocytes migrated or nerve fiber growth were observed. However, in β-xyloside-treated cultures, the confluency of astrocytic monolayer was disrupted. In E18 cultures both early and late treatments, neuronal migration was present in control cultures, which was preserved using ChABC but not β-xyloside. In conclusion, ChABC and β-xyloside had similar effects and hampered nerve fiber growth and astrocytic migration in E14 cultures. In E18 cultures nerve fiber growth was stimulated and neuronal migration was hampered after β-xyloside treatment while ChABC treatment did not exert these effects.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
CSPGs; Spinal cord; Ventral mesencephalon; ChABC; β-xyloside
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-87978 (URN)10.1016/j.brainres.2014.03.043 (DOI)000336703900003 ()
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2018-01-11Bibliographically approved
Chermenina, M., Schouten, P., Nevalainen, N., Johansson, F., Orädd, G. & Strömberg, I. (2014). GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum. Neuroscience, 270, 1-11.
Open this publication in new window or tab >>GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum
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2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 270, 1-11 p.Article in journal (Refereed) Published
Abstract [en]

Glial cell-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.

Keyword
GDNF, GDNF knockout, dopamine, substantia nigra, striatum, DARPP-32
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-88075 (URN)10.1016/j.neuroscience.2014.04.008 (DOI)000336624000001 ()24726488 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2018-01-11Bibliographically approved
Virel, A., Faergemann, E., Orädd, G. & Strömberg, I. (2014). Magnetic Resonance Imaging (MRI) to Study Striatal Iron Accumulation in a Rat Model of Parkinson's Disease. PLoS ONE, 9(11), e112941.
Open this publication in new window or tab >>Magnetic Resonance Imaging (MRI) to Study Striatal Iron Accumulation in a Rat Model of Parkinson's Disease
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, e112941- p.Article in journal (Refereed) Published
Abstract [en]

Abnormal accumulation of iron is observed in neurodegenerative disorders. In Parkinson's disease, an excess of iron has been demonstrated in different structures of the basal ganglia and is suggested to be involved in the pathogenesis of the disease. Using the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, the edematous effect of 6-OHDA and its relation with striatal iron accumulation was examined utilizing in vivo magnetic resonance imaging (MRI). The results revealed that in comparison with control animals, injection of 6-OHDA into the rat striatum provoked an edematous process, visible in T2-weighted images that was accompanied by an accumulation of iron clearly detectable in T2*-weighted images. Furthermore, Prussian blue staining to detect iron in sectioned brains confirmed the existence of accumulated iron in the areas of T2* hypointensities. The presence of ED1-positive microglia in the lesioned striatum overlapped with this accumulation of iron, indicating areas of toxicity and loss of dopamine nerve fibers. Correlation analyses demonstrated a direct relation between the hyperintensities caused by the edema and the hypointensities caused by the accumulation of iron.

National Category
Radiology, Nuclear Medicine and Medical Imaging Neurosciences
Identifiers
urn:nbn:se:umu:diva-98441 (URN)10.1371/journal.pone.0112941 (DOI)000345558500115 ()25398088 (PubMedID)2-s2.0-84911902551 (Scopus ID)
Available from: 2015-02-04 Created: 2015-01-22 Last updated: 2018-01-11Bibliographically approved
Nevalainen, N., Af Bjerkén, S., Gerhardt, G. A. & Strömberg, I. (2014). Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia. Neuroscience, 260, 73-86.
Open this publication in new window or tab >>Serotonergic nerve fibers in l-DOPA-derived dopamine release and dyskinesia
2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 260, 73-86 p.Article in journal (Refereed) Published
Abstract [en]

The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (∼30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.

Place, publisher, year, edition, pages
Elsevier, 2014
Keyword
l-DOPA, dyskinesia, 5-HT, in vivo chronoamperometry, fluoxetine, WAY-100 635
National Category
Neurosciences Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-84741 (URN)10.1016/j.neuroscience.2013.12.029 (DOI)000330598100007 ()24361918 (PubMedID)
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2018-01-11Bibliographically approved
Hohsfield, L. A., Daschil, N., Orädd, G., Strömberg, I. & Humpel, C. (2014). Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models. Molecular and cellular neuroscience, 63, 83-95.
Open this publication in new window or tab >>Vascular pathology of 20-month-old hypercholesterolemia mice in comparison to triple-transgenic and APPSwDI Alzheimer's disease mouse models
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2014 (English)In: Molecular and cellular neuroscience, ISSN 1044-7431, Vol. 63, 83-95 p.Article in journal (Refereed) Published
Abstract [en]

Several studies have shown that elevated plasma cholesterol levels (i.e. hypercholesterolemia) serve as a risk factor for late-onset Alzheimer's disease (AD). However, it remains unclear how hypercholesterolemia may contribute to the onset and progression of AD pathology. In order to determine the role of hypercholesterolemia at various stages of AD, we evaluated the effects of high cholesterol diet (5% cholesterol) in wild-type (WT; C57BL6) and triple-transgenic AD (3xTg-AD: Psen1, APPSwe, tauB301L) mice at 7, 14, and 20 months. The transgenic APP-Swedish/Dutch/Iowa AD mouse model (APPSwDI) was used as a control since these animals are more pathologically-accelerated and are known to exhibit extensive plaque deposition and cerebral amyloid angiopathy. Here, we describe the effects of high cholesterol diet on: (1) cognitive function and stress, (2) AD-associated pathologies, (3) neuroinflammation, (4) blood-brain barrier disruption and ventricle size, and (5) vascular dysfunction. Our data show that high dietary cholesterol increases weight, slightly impairs cognitive function, promotes glial cell activation and complement-related pathways, enhances the infiltration of blood-derived proteins and alters vascular integrity, however, it does not induce AD-related pathologies. While normal-fed 3xTg-AD mice display a typical AD-like pathology in addition to severe cognitive impairment and neuroinflammation at 20 months of age, vascular alterations are less pronounced. No microbleedings were seen by MRI, however, the ventricle size was enlarged. Triple-transgenic AD mice, on the other hand, fed a high cholesterol diet do not survive past 14 months of age. Our data indicates that cholesterol does not markedly potentiate AD-related pathology, nor does it cause significant impairments in cognition. However, it appears that high cholesterol diet markedly increases stress-related plasma corticosterone levels as well as some vessel pathologies. Together, our findings represent the first demonstration of prolonged high cholesterol diet and the examination of its effects at various stages of cerebrovascular- and AD-related disease.

Place, publisher, year, edition, pages
Academic Press, 2014
Keyword
Alzheimer's disease, hypercholesterolemia, cholesterol, β-amyloid, tau, neuroinflammation, scular pathology, learning, memory, MRI
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-97896 (URN)10.1016/j.mcn.2014.10.006 (DOI)000346227200009 ()
Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2018-01-11Bibliographically approved
Strömberg, I., Rehnmark, A., Orädd, G. & Virel, A. (2013). Neuroinflammation Using MRI: Phagocytes From Blood to Brain With the Help of Bilberries. Cell Transplantation, 22(5), 917-917.
Open this publication in new window or tab >>Neuroinflammation Using MRI: Phagocytes From Blood to Brain With the Help of Bilberries
2013 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 5, 917-917 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-73089 (URN)000318585300084 ()
Available from: 2013-06-17 Created: 2013-06-17 Last updated: 2017-12-06Bibliographically approved
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