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Zysk, M., Clausen, F., Aguilar, X., Sehlin, D., Syvänen, S. & Erlandsson, A. (2019). Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 72(1), 161-180
Open this publication in new window or tab >>Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 161-180Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-beta (A beta) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A beta pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

Place, publisher, year, edition, pages
IOS PRESS, 2019
Keywords
Alzheimer's disease, amyloid-beta, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-400408 (URN)10.3233/JAD-190572 (DOI)000500780700014 ()31561367 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Stenler, S., Roshanbin, S., Yilmaz Ugur, C., Rostami, J., Aguilar, X., Erlandsson, A., . . . Hultqvist, G. (2019). Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease. In: : . Paper presented at 15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019.
Open this publication in new window or tab >>Over the BBB and into the cell: Pursuing intracellular targets for immunotherapy of Parkinson’s disease
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

The aim of our research is to modify therapeutic antibodies so that they can reach their dementia target inside cells located on the other side of the blood brain barrier. While the aggregates associated with Alzheimer’s are located extracellularly and thus readily available for antibodies that have crossed the BBB barrier, this is not the case for Parkinson’s disease. In this study, we focus on developing a peptide shuttle that can deliver antibodies not only over the BBB but also into neuronal cells where the Tau and a-synuclein aggregates can be found.

For this purpose, we have investigated the use of a peptide which binds to a receptor that co- localizes with the aggregates. Our in-house experience suggests that the peptide is not an efficient BBB transporter despite the fact that some groups have used it as such, but that it might be more suitable as a transporter for intracellular delivery.

We have successfully expressed recombinant antibodies with the peptide on the N-terminal of an antibody targeting the aggregates associated with Parkinson’s disease. Our initial studies indicate that the tyrosine on the N-terminal of the peptide needs to be free and unmodified to be able to enhance uptake into neuronal cells. This hinders the use of the normal labelling method which attaches radiolabelled iodine to tyrosines where the affinity for peptide target would be destroyed. We have been pursuing alternative methods, such as using click chemistry to attach the peptide which will leave the antibody free to be radiolabelled, as well as methods to detect unlabelled antibodies in vivo and in vitro.

We have assessed the peptide-assisted increase in uptake in appropriate neuronal cell line models. Furthermore, we have studied uptake and retention in brain in mouse models for Parkinson’s disease.

Keywords
Protein drug design, blood-brain-barrier, neurodegenerative diseases, immunotherapy, antibody-based drugs
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-401539 (URN)
Conference
15th annual PEGS: The Essential Protein Engineering & Cell Therapy Summit, Boston, USA, April 8-12 2019
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-22Bibliographically approved
Olsen, M., Aguilar, X., Sehlin, D., Fang, X. T., Antoni, G., Erlandsson, A. & Syvänen, S. (2018). Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease. Molecular Imaging and Biology, 20(4), 605-614
Open this publication in new window or tab >>Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease
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2018 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 20, no 4, p. 605-614Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (A beta) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[C-11]deprenyl ([C-11]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during A beta pathology progression. APP(ArcSwe) mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C-11]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. A beta and GFAP levels were also measured with ELISA in brain homogenates. The intrabrain levels of aggregated A beta and reactive astrocytes were found to be elevated in APP(ArcSwe) compared with WT mice. GFAP and vimentin expression increased with age, i.e., with A beta pathology, in the APP(ArcSwe) mice. This was not the case for in vivo marker [C-11]DED that showed elevated binding of the same magnitude in APP(ArcSwe) mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. MAO-B levels are increased early in A beta pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant A beta plaque formation. Thus, [C-11]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of A beta pathology.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
PET, Amyloid-beta, Astrocytes, Astrogliosis, MAO-B, GFAP, Vimentin, [C-11]DED
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-361033 (URN)10.1007/s11307-017-1153-z (DOI)000438457800010 ()29297157 (PubMedID)
Funder
The Swedish Brain FoundationGun och Bertil Stohnes Stiftelse
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved
Ekmark-Lewén, S., Lindstrom, V., Gumucio, A., Ihse, E., Behere, A., Kahle, P. J., . . . Ingelsson, M. (2018). Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice. Brain and Behavior, 8(3), Article ID e00915.
Open this publication in new window or tab >>Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice
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2018 (English)In: Brain and Behavior, ISSN 2162-3279, E-ISSN 2162-3279, Vol. 8, no 3, article id e00915Article in journal (Refereed) Published
Abstract [en]

Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other a-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points.

Methods: We analyzed gait deficits, locomotion, and behavioral profiles in (Thy-1)-h[A30P] alpha-synuclein and control mice at 2, 8, and 11 months of age. In addition, inflammatory markers, levels of alpha-synuclein oligomers, and tyrosine hydroxylase reactivity were studied.

Results: Already at 2 months of age, transgenic mice displayed fine motor impairments in the challenging beam test that progressively increased up to 11 months of age. At 8 months, transgenic mice showed a decreased general activity with increased risk-taking behavior in the multivariate concentric square field test. Neuropathological analyses of 8- and 11-month-old mice revealed accumulation of oligomeric alpha-synuclein in neuronal cell bodies. In addition, a decreased presence of tyrosine hydroxylase suggests a dysregulation of the dopaminergic system in the transgenic mice, which in turn may explain some of the motor impairments observed in this mouse model.

Conclusions: Taken together, our results show that the (Thy-1)-h[A30P] alpha-synuclein transgenic mouse model displays early Parkinson's disease-related symptoms with a concomitant downregulation of the dopaminergic system. Thus, this should be an -appropriate model to study early phenotypes of alpha-synucleinopathies.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
A30P mutation, alpha-synuclein, behavioral outcome, challenging beam test, dementia with Lewy bodies, Helicobacter pylori, multivariate concentric square field test, Parkinson' s disease, transgenic mice, tyrosine hydroxylase
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-350297 (URN)10.1002/brb3.915 (DOI)000426762600005 ()29541535 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationThe Dementia Association - The National Association for the Rights of the DementedMarianne and Marcus Wallenberg FoundationMagnus Bergvall Foundation
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-05-09Bibliographically approved
Almandoz-Gil, L., Persson, E., Lindström, V., Ingelsson, M., Erlandsson, A. & Bergström, J. (2018). In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons. Frontiers in Neurology, 9, Article ID 180.
Open this publication in new window or tab >>In situ proximity ligation assay reveals co-localization of alpha-synuclein and SNARE proteins in murine primary neurons
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2018 (English)In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 180Article in journal (Refereed) Published
Abstract [en]

The aggregation of alpha-synuclein (alpha Syn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of aSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between aSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human aSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human aSyn, a PLA signal indicating close proximity between aSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non-transgenic and transgenic neurons. With an antibody specific against human aSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of aSyn and the SNARE proteins in primary neuronal cultures

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-342580 (URN)10.3389/fneur.2018.00180 (DOI)000428063500001 ()29623065 (PubMedID)
Funder
Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Society of MedicineMagnus Bergvall Foundation
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-06-28Bibliographically approved
Zysk, M., Gapys, B., Ronowska, A., Gul-Hinc, S., Erlandsson, A., Iwanicki, A., . . . Bielarczyk, H. (2018). Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells. PLoS ONE, 13(12), Article ID e0209363.
Open this publication in new window or tab >>Protective effects of voltage-gated calcium channel antagonists against zinc toxicity in SN56 neuroblastoma cholinergic cells
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209363Article in journal (Refereed) Published
Abstract [en]

One of the pathological site effects in excitotoxic activation is Zn2+ overload to postsynaptic neurons. Such an effect is considered to be equivalent to the glutamate component of excitotoxicity. Excessive uptake of Zn2+ by active voltage-dependent transport systems in these neurons may lead to significant neurotoxicity. The aim of this study was to investigate whether and which antagonists of the voltage gated calcium channels (VGCC) might modify this Zn2+-induced neurotoxicity in neuronal cells. Our data demonstrates that depolarized SN56 neuronal cells may take up large amounts of Zn2+ and store these in cytoplasmic and mitochondrial sub-fractions. The mitochondrial Zn2+ excess suppressed pyruvate uptake and oxidation. Such suppression was caused by inhibition of pyruvate dehydrogenase complex, aconitase and NADP-isocitrate dehydrogenase activities, resulting in the yielding of acetyl-CoA and ATP shortages. Moreover, incoming Zn2+ increased both oxidized glutathione and malondialdehyde levels, known parameters of oxidative stress. In depolarized SN56 cells, nifedipine treatment (L-type VGCC antagonist) reduced Zn2+ uptake and oxidative stress. The treatment applied prevented the activities of PDHC, aconitase and NADP-IDH enzymes, and also yielded the maintenance of acetyl-CoA and ATP levels. Apart from suppression of oxidative stress, N- and P/Q-type VGCCs presented a similar, but weaker protective influence. In conclusion, our data shows that in the course of excitotoxity, impairment to calcium homeostasis is tightly linked with an excessive neuronal Zn2+ uptake. Hence, the VGCCs types L, N and P/Q share responsibility for neuronal Zn2+ overload followed by significant energy-dependent neurotoxicity. Moreover, Zn2+ affects the target tricarboxylic acid cycle enzymes, yields acetyl-CoA and energy deficits as well.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-373231 (URN)10.1371/journal.pone.0209363 (DOI)000453841700061 ()30571745 (PubMedID)
Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Gustafsson, G., Lööv, C., Persson, E., Lázaro, D. F., Takeda, S., Bergström, J., . . . Ingelsson, M. (2018). Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells. Cellular and molecular neurobiology, 38(8), 1539-1550
Open this publication in new window or tab >>Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells
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2018 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed) Published
Abstract [en]

In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells. Different α-syn variants, including α-syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted α-syn, 0.1–2% was associated with vesicles. The major part of EV α-syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For α-syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT α-syn. Moreover, such EV-associated α-syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T α-syn displayed an increased association with EVs. Taken together, our data suggest that α-syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful α-syn species and thereby contribute to the pathology in α-synucleinopathies.

National Category
Other Medical Sciences Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:uu:diva-326117 (URN)10.1007/s10571-018-0622-5 (DOI)000449258300008 ()30288631 (PubMedID)
Funder
Swedish Research Council, 2011-4519Swedish Research Council, 2012-2172Swedish Research Council, 2010-6745Swedish Research Council, 2013-2735Marianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationHans-Gabriel och Alice Trolle-Wachtmeisters stiftelse för medicinsk forskningSwedish Society of MedicineGun och Bertil Stohnes StiftelseStiftelsen Söderström - Königska sjukhemmetThe Dementia Association - The National Association for the Rights of the DementedStiftelsen Gamla TjänarinnorNIH (National Institute of Health)German Research Foundation (DFG)
Available from: 2017-07-05 Created: 2017-07-05 Last updated: 2018-12-19Bibliographically approved
Söllvander, S., Nikitidou, E., Gallasch, L., Zysk, M., Söderberg, L., Sehlin, D., . . . Erlandsson, A. (2018). The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta-induced cell death. Journal of Neuroinflammation, 15, Article ID 98.
Open this publication in new window or tab >>The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta-induced cell death
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 98Article in journal (Refereed) Published
Abstract [en]

Background: Currently, several amyloid beta (A beta) antibodies, including the protofibril selective antibody BAN2401, are in clinical trials. The murine version of BAN2401, mAb158, has previously been shown to lower the levels of pathogenic A beta and prevent A beta deposition in animal models of Alzheimer's disease (AD). However, the cellular mechanisms of the antibody's action remain unknown. We have recently shown that astrocytes effectively engulf A beta(42) protofibrils, but store rather than degrade the ingested A beta aggregates. In a co-culture set-up, the incomplete degradation of A beta(42) protofibrils by astrocytes results in increased neuronal cell death, due to the release of extracellular vesicles, containing N-truncated, neurotoxic A beta. Methods: The aim of the present study was to investigate if the accumulation of A beta in astrocytes can be affected by the A beta protofibril selective antibody mAb158. Co-cultures of astrocytes, neurons, and oligodendrocytes, derived from embryonic mouse cortex, were exposed to A beta(42) protofibrils in the presence or absence of mAb158. Results: Our results demonstrate that the presence of mAb158 almost abolished A beta accumulation in astrocytes. Consequently, mAb158 treatment rescued neurons from A beta-induced cell death. Conclusion: Based on these findings, we conclude that astrocytes may play a central mechanistic role in anti-A beta immunotherapy.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Alzheimer's disease, Amyloid-beta, Antibody, Clearance, Astrocyte, Neuron
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-354346 (URN)10.1186/s12974-018-1134-4 (DOI)000428573400001 ()29592816 (PubMedID)
Funder
Swedish Research Council, 2012-2172Magnus Bergvall Foundation
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31Bibliographically approved
Gustafsson, G., Lindström, V., Rostami, J., Nordström, E., Lannfelt, L., Bergström, J., . . . Erlandsson, A. (2017). Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes. Journal of Neuroinflammation, 14, Article ID 241.
Open this publication in new window or tab >>Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes
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2017 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, article id 241Article in journal (Refereed) Published
Abstract [en]

Background: Due to its neurotoxic properties, oligomeric alpha-synuclein (α-syn) has been suggested as an attractive target for passive immunization against Parkinson’s disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic α-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf α-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria.

Methods: The aim of the present study was to investigate if the accumulation of α-syn in astrocytes can be affected by α-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to α-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies.

Results: In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added α-syn, and consequently, the α-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer-induced mitochondrial impairment.

Conclusions: Our results demonstrate that oligomer-selective antibodies can prevent α-syn accumulation and mitochondrial dysfunction in cultured astrocytes.

Keywords
alpha-synuclein oligomers, Astrocytes, Antibodies, Mitochondria, Lysosomal degradation, Parkinson's disease
National Category
Geriatrics Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-339802 (URN)10.1186/s12974-017-1018-z (DOI)000417882800002 ()29228971 (PubMedID)
Funder
Swedish Research CouncilMarianne and Marcus Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-02-23Bibliographically approved
Lindström, V., Gustafsson, G., Sanders, L. H., Howlett, E. H., Sigvardson, J., Kasrayan, A., . . . Erlandsson, A. (2017). Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Molecular and Cellular Neuroscience, 82, 143-156
Open this publication in new window or tab >>Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage
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2017 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 82, p. 143-156Article in journal (Refereed) Published
Abstract [en]

The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently in astrocytes. However, the pathological significance of α-synuclein inclusions in astrocytes and the capacity of glial cells to clear toxic α-synuclein species remain unknown. In the present study we investigated uptake, degradation and toxic effects of oligomeric α-synuclein in a co-culture system of primary neurons, astrocytes and oligodendrocytes. Alpha-synuclein oligomers were found to co-localize with the glial cells and the astrocytes were found to internalize particularly large amounts of the protein. Following ingestion, the astrocytes started to degrade the oligomers via the lysosomal pathway but, due to incomplete digestion, large intracellular deposits remained. Moreover, the astrocytes displayed mitochondrial abnormalities. Taken together, our data indicate that astrocytes play an important role in the clearance of toxic α-synuclein species from the extracellular space. However, when their degrading capacity is overburdened, α-synuclein deposits can persist and result in detrimental cellular processes.

Keywords
Astrocytes, Glia, Mitochondria, Oligodendrocytes, Parkinson's disease, α-Synuclein oligomers
National Category
Other Medical Sciences
Research subject
Medical Science; Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-326114 (URN)10.1016/j.mcn.2017.04.009 (DOI)000405977400015 ()28450268 (PubMedID)
Funder
Swedish Research Council, 2015-02671Magnus Bergvall Foundation, 2016-01714Marianne and Marcus Wallenberg FoundationThe Swedish Brain Foundation
Available from: 2017-07-02 Created: 2017-07-02 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7292-1608

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