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  • 1.
    Ekmark-Lewén, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Flygt, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Kiwanuka, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes2013In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 10, no 1, p. 44-Article in journal (Refereed)
    Abstract [en]

    Background

    Diffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the murine central fluid percussion injury (cFPI) TAI model, the neuroinflammatory and astroglial response and behavioral changes are unknown.

    Methods

    Twenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).

    Results

    At all post-injury time points, beta-amyloid precursor protein (beta-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood--brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.

    Conclusions

    Traumatic axonal injury in mice resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting traumatic axonal injury.

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  • 2.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lu, Binfeng
    Harris, Robert A
    Magnusson, Peetra U
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loskog, Angelica Si
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery2012In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, p. 112-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.

    METHODS

    CD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.

    RESULTS

    The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.

    CONCLUSION

    CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.

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  • 3.
    Gard, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Neurosurg, Lund, Sweden..
    Vedung, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Piehl, Fredrik
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden..
    Khademi, Mohsen
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, Stockholm, Sweden..
    Wernersson, Maria Portonova
    Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden..
    Rorsman, Ia
    Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden..
    Tegner, Yelverton
    Luleå Univ Technol, Dept Hlth Sci, Luleå, Sweden..
    Pessah-Rasmussen, Helene
    Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden.;Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden..
    Ruscher, Karsten
    Lund Univ, Dept Clin Sci Lund, Neurosurg, Lund, Sweden..
    Marklund, Niklas
    Lund Univ, Dept Clin Sci Lund, Neurosurg, Lund, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurosurg, EA Blocket Plan 4,Klinikgatan 17A7, S-22185 Lund, Sweden..
    Cerebrospinal fluid levels of neuroinflammatory biomarkers are increased in athletes with persistent post-concussive symptoms following sports-related concussion2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 189Article in journal (Refereed)
    Abstract [en]

    A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for & GE; 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising & LE; 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-& alpha;, IL-15, TNF-& beta;, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < - 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.

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  • 4.
    Gustafsson, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindström, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rostami, Jinar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordström, Eva
    BioArct AB, Stockholm.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes2017In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, article id 241Article in journal (Refereed)
    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.

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  • 5. Kenne, Ellinor
    et al.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lindbom, Lennart
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice2012In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, p. 17-Article in journal (Refereed)
    Abstract [en]

    Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear.

    Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data.

    Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury.

    Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice.

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  • 6.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    Background

    Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated.

    Methods

    In this study, we aimed to investigate how intracellular deposits of Aβ in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils. The direct and indirect effects of the Αβ-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte–neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.

    Results

    Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with Aβ-exposed astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with Aβ deposits led to an elevated clearance of dead cells in the co-cultures.

    Conclusions

    Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactive state of the astrocytes, as well as their ability to support neuronal function.

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  • 7. Lindblom, Rickard P F
    et al.
    Aeinehband, Shahin
    Parsa, Roham
    Ström, Mikael
    Al Nimer, Faiez
    Zhang, Xing-Mei
    Dominguez, Cecilia A
    Flytzani, Sevasti
    Diez, Margarita
    Piehl, Fredrik
    Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.2013In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection.

    METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains.

    RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury.

    CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.

  • 8.
    Lindblom, Rickard P. F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery. Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Neuroimmunol Unit CMM L8 04, S-17176 Stockholm, Sweden..
    Berg, Alexander
    Karolinska Inst, Div Neuronal Regenerat, Dept Neurosci, Stockholm, Sweden..
    Strom, Mikael
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Aeinehband, Shahin
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Dominguez, Cecilia A.
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Al Nimer, Faiez
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Abdelmagid, Nada
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Heinig, Matthias
    Max Delbruck Ctr Mol Med, Expt Genet Cardiovasc Dis, Berlin, Germany..
    Zelano, Johan
    Karolinska Inst, Div Neuronal Regenerat, Dept Neurosci, Stockholm, Sweden..
    Harnesk, Karin
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Hubner, Norbert
    Max Delbruck Ctr Mol Med, Expt Genet Cardiovasc Dis, Berlin, Germany..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Diez, Margarita
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Cullheim, Staffan
    Karolinska Inst, Div Neuronal Regenerat, Dept Neurosci, Stockholm, Sweden..
    Piehl, Fredrik
    Karolinska Inst, Neuroimmunol Unit, Dept Clin Neurosci, Stockholm, Sweden..
    Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response2015In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 12, article id 192Article in journal (Refereed)
    Abstract [en]

    Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.

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  • 9.
    Magnúsdóttir, Elín Ingibjörg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    Grujic, Mirjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Lagerström, Malin C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Lagerström: Sensory circuits.
    Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-12020In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, article id 123Article in journal (Refereed)
    Abstract [en]

    Background: Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ET(A)Rs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch.

    Methods: In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed.

    Results: CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect.

    Conclusion: Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1.

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  • 10.
    Mazzeo, Anna Teresa
    et al.
    Univ Turin, Dept Surg Sci, Anesthesia & Intens Care Unit, Turin, Italy..
    Filippini, Claudia
    Univ Turin, Dept Surg Sci, Turin, Italy..
    Rosato, Rosalba
    Univ Turin, Dept Psychol, Turin, Italy..
    Fanelli, Vito
    Univ Turin, Dept Surg Sci, Anesthesia & Intens Care Unit, Turin, Italy..
    Assenzio, Barbara
    Univ Turin, Dept Surg Sci, Anesthesia & Intens Care Unit, Turin, Italy..
    Piper, Ian
    So Gen Hosp, Dept Clin Phys, Glasgow, Lanark, Scotland..
    Howells, Timothy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mastromauro, Ilaria
    Univ Turin, Dept Surg Sci, Anesthesia & Intens Care Unit, Turin, Italy..
    Berardino, Maurizio
    AOU Citta Salute & Sci Torino, Presidio CTO, Anesthesia & Intens Care Unit, Turin, Italy..
    Ducati, Alessandro
    Univ Turin, Dept Neurosci, Neurosurg Unit, Turin, Italy..
    Mascia, Luciana
    Univ Roma La Sapienza, Dipartimento Sci & Biotecnol Med Chirurg, Rome, Italy..
    Multivariate projection method to investigate inflammation associated with secondary insults and outcome after human traumatic brain injury: a pilot study2016In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 13, article id 157Article in journal (Refereed)
    Abstract [en]

    Background: Neuroinflammation has been proposed as a possible mechanism of brain damage after traumatic brain injury (TBI), but no consensus has been reached on the most relevant molecules. Furthermore, secondary insults occurring after TBI contribute to worsen neurological outcome in addition to the primary injury. We hypothesized that after TBI, a specific pattern of cytokines is related to secondary insults and outcome. Methods: A prospective observational clinical study was performed. Secondary insults by computerized multimodality monitoring system and systemic value of different cytokines were collected and analysed in the first week after intensive care unit admission. Neurological outcome was assessed at 6 months (GOSe). Multivariate projection technique was applied to analyse major sources of variation and collinearity within the cytokines dataset without a priori selecting potential relevant molecules. Results: Twenty-nine severe traumatic brain injury patients undergoing intracranial pressure monitoring were studied. In this pilot study, we demonstrated that after TBI, patients who suffered of prolonged and severe secondary brain damage are characterised by a specific pattern of cytokines. Patients evolving to brain death exhibited higher levels of inflammatory mediators compared to both patients with favorable and unfavorable neurological outcome at 6 months. Raised ICP and low cerebral perfusion pressure occurred in 21 % of good monitoring time. Furthermore, the principal components selected by multivariate projection technique were powerful predictors of neurological outcome. Conclusions: The multivariate projection method represents a valuable methodology to study neuroinflammation pattern occurring after secondary brain damage in severe TBI patients, overcoming multiple putative interactions between mediators and avoiding any subjective selection of relevant molecules.

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  • 11.
    Pikwer, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Mälarsjukhuset.
    Castegren, Markus
    Karolinska Univ Hosp, Perioperat Med & Intens Care PMI, Stockholm, Sweden.;Karolinska Inst, Clintec, Stockholm, Sweden..
    Namdar, Sijal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Mälarsjukhuset.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;UCL, Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England..
    Mattsson, Niklas
    Lund Univ, Clin Memory Res Unit, Fac Med, Lund, Sweden.;Skane Univ Hosp, Dept Neurol, Lund, Sweden..
    Effects of surgery and propofol-remifentanil total intravenous anesthesia on cerebrospinal fluid biomarkers of inflammation, Alzheimer's disease, and neuronal injury in humans: a cohort study2017In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 14, article id 193Article in journal (Refereed)
    Abstract [en]

    Background: Surgery and anesthesia have been linked to postoperative cognitive disturbance and increased risk of Alzheimer's disease. It is not clear by which mechanisms this increased risk for cognitive disease is mediated. Further, amyloid beta production has been suggested to depend on the sleep-wake cycle and neuronal activity. The aim of the present study was to examine if cerebrospinal fluid (CSF) concentrations of a number of biomarkers for Alzheimer's disease-related processes, including amyloid beta, neuronal injury, and inflammation, changed over time during intravenous anesthesia in surgical patients. Methods: We included patients scheduled for hysterectomy via laparotomy during general anesthesia with intravenous propofol and remifentanil. CSF samples were obtained before, during, and after surgery (5 h after induction) and tested for 27 biomarkers. Changes over time were tested with linear mixed effects models. Results: A total of 22 patients, all females, were included. The mean age was 50 years (+/- 9 SD). The mean duration of the anesthesia was 145 min (+/- 40 SD). Interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and vascular endothelial growth factor A increased over time. IL-15 and IL-7 decreased slightly over time. Macrophage inflammatory protein 1 beta and placental growth factor also changed significantly. There were no significant effects on amyloid beta (A beta) or tau biomarkers. Conclusions: Surgery and general anesthesia with intravenous propofol and remifentanil induce, during and in the short term after the procedure, a neuroinflammatory response which is dominated by monocyte attractants, without biomarker signs of the effects on Alzheimer's disease pathology or neuronal injury.

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  • 12. Ramberg, Veronica
    et al.
    Tracy, Linda M.
    Samuelsson, Malin
    Nilsson, Lars N. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Iverfeldt, Kerstin
    The CCAAT/enhancer binding protein (C/EBP) delta is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-beta peptide2011In: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 8, p. 34-Article in journal (Refereed)
    Abstract [en]

    Background: The transcription factors CCAAT/enhancer binding proteins (C/EBP) alpha, beta and delta have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor kappa B (NF-kappa B). In general, C/EBP alpha is down-regulated, whereas both C/EBP beta and delta are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-beta (A beta) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Ab deposits with the aim of defining new therapeutic targets. Methods: Here we have investigated the effects of A beta on expression of C/EBP family members with a focus on C/EBP delta in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar A beta deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBP delta and NF-kappa B was investigated by analyzing binding to a kappa B site using a biotin streptavidin-agarose pull-down assay. Results: We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of A beta inhibit upregulation of C/EBP delta expression in interleukin-1 beta-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBP alpha was significantly down-regulated and C/EBP beta was significantly up-regulated. C/EBP beta, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar A beta deposits. In contrast, no difference in expression levels of C/EBP delta between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1 beta-induced C/EBP delta DNA binding activity to both C/EBP and kappa B sites is abolished after exposure to A beta. Conclusions: These data suggest that both expression and function of C/EBP delta are dysregulated in Alzheimer's disease. C/EBP delta seems to be differently regulated in response to different conformations of A beta. We propose that A beta induces an imbalance between NF-kappa B and C/EBP transcription factors that may result in abnormal responses to inflammatory stimuli.

  • 13.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sirois, Julien
    Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
    Mzezewa, Ropafadzo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Healy, Luke
    Neuroimmunology Unit, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson's disease brain2020In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 17, no 1, article id 119Article in journal (Refereed)
    Abstract [en]

    Background

    Many lines of evidence suggest that accumulation of aggregated alpha-synuclein (αSYN) in the Parkinson’s disease (PD) brain causes infiltration of T cells. However, in which ways the stationary brain cells interact with the T cells remain elusive. Here, we identify astrocytes as potential antigen-presenting cells capable of activating T cells in the PD brain. Astrocytes are a major component of the nervous system, and accumulating data indicate that astrocytes can play a central role during PD progression.

    Methods

    To investigate the role of astrocytes in antigen presentation and T-cell activation in the PD brain, we analyzed post mortem brain tissue from PD patients and controls. Moreover, we studied the capacity of cultured human astrocytes and adult human microglia to act as professional antigen-presenting cells following exposure to preformed αSYN fibrils.

    Results

    Our analysis of post mortem brain tissue demonstrated that PD patients express high levels of MHC-II, which correlated with the load of pathological, phosphorylated αSYN. Interestingly, a very high proportion of the MHC-II co-localized with astrocytic markers. Importantly, we found both perivascular and infiltrated CD4+ T cells to be surrounded by MHC-II expressing astrocytes, confirming an astrocyte T cell cross-talk in the PD brain. Moreover, we showed that αSYN accumulation in cultured human astrocytes triggered surface expression of co-stimulatory molecules critical for T-cell activation, while cultured human microglia displayed very poor antigen presentation capacity. Notably, intercellular transfer of αSYN/MHC-II deposits occurred between astrocytes via tunneling nanotubes, indicating spreading of inflammation in addition to toxic protein aggregates.

    Conclusions

    In conclusion, our data from histology and cell culture studies suggest an important role for astrocytes in antigen presentation and T-cell activation in the PD brain, highlighting astrocytes as a promising therapeutic target in the context of chronic inflammation.

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  • 14.
    Rostami, Jinar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kolahdouzan, Mahshad
    Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Moslem, Mohsen
    Department of Neuroscience, Karolinska Institutet.
    Bergström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Healy, Luke M.
    Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University.
    Falk, Anna
    Karolinska institutet.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates2021In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 18, no 1, article id 124Article in journal (Refereed)
    Abstract [en]

    Background

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.

    Methods

    The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized “close-culture” chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.

    Results

    Our data show that intracellular deposits of αSYN and Aβ are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the “close-culture” chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.

    Conclusions

    Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.

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  • 15.
    Söllvander, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikitidou, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zysk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Söderberg, Linda
    BioArctic AB, Warfvinges Vag 35, SE-11251 Stockholm, Sweden.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta-induced cell death2018In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 98Article in journal (Refereed)
    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.

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  • 16.
    Zhou, Kai
    et al.
    Zhengzhou Univ, Childrens Hosp, Henan Neurodev Engn Res Ctr Children, Zhengzhou, Peoples R China.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Han, Jinming
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci,Appl Immunol & Immunotherapy, Stockholm, Sweden.;Capital Med Univ, Natl Ctr Neurol Disorders, Xuanwu Hosp, Neuroimmunol Ctr,Dept Neurol, Beijing, Peoples R China..
    Lund, Harald
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci,Appl Immunol & Immunotherapy, Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Boggavarapu, Nageswara Rao
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.;Univ Tubingen, Tubingen, Germany..
    Goto, Shinobu
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Nagoya City Univ Hosp, Dept Obstet & Gynecol, Nagoya, Aichi, Japan..
    Cheng, Huaitao
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Wang, Yuyu
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Tachi, Asuka
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Nagoya Univ, Grad Sch Med, Dept Obstet & Gynecol, Nagoya, Aichi, Japan..
    Xie, Cuicui
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Zhu, Keying
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci,Appl Immunol & Immunotherapy, Stockholm, Sweden..
    Sun, Ying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Osman, Ahmed M.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Liang, Dong
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Han, Wei
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Gemzell-Danielsson, Kristina
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, WHO Ctr, Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Huddinge, Sweden..
    Zhang, Xing-Mei
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci,Appl Immunol & Immunotherapy, Stockholm, Sweden..
    Zhu, Changlian
    Univ Gothenburg, Inst Neurosci & Physiol, Ctr Brain Repair & Rehabil, Gothenburg, Sweden.;Zhengzhou Univ, Affiliated Hosp 3, Henan Key Lab Child Brain Injury, Zhengzhou, Peoples R China.;Zhengzhou Univ, Affiliated Hosp 3, Henan Pediat Clin Res Ctr, Zhengzhou, Peoples R China.;Zhengzhou Univ, Inst Neurosci, Zhengzhou, Peoples R China..
    Enge, Martin
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Joseph, Bertrand
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Harris, Robert A.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci,Appl Immunol & Immunotherapy, Stockholm, Sweden..
    Blomgren, Klas
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Zhengzhou Univ, Affiliated Hosp 3, Henan Key Lab Child Brain Injury, Zhengzhou, Peoples R China.;Zhengzhou Univ, Affiliated Hosp 3, Henan Pediat Clin Res Ctr, Zhengzhou, Peoples R China.;Zhengzhou Univ, Inst Neurosci, Zhengzhou, Peoples R China.;Karolinska Univ Hosp, Pediat Oncol, Stockholm, Sweden..
    An overlooked subset of Cx3cr1(wt/wt) microglia in the Cx3cr1(CreER-Eyfp/wt) mouse has a repopulation advantage over Cx3cr1(CreER-Eyfp/wt) microglia following microglial depletion2022In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 19, no 1, article id 20Article in journal (Refereed)
    Abstract [en]

    Background Fluorescent reporter labeling and promoter-driven Cre-recombinant technologies have facilitated cellular investigations of physiological and pathological processes, including the widespread use of the Cx3cr1(CreER-Eyfp/wt) mouse strain for studies of microglia. Methods Immunohistochemistry, Flow Cytometry, RNA sequencing and whole-genome sequencing were used to identify the subpopulation of microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains. Genetically mediated microglia depletion using Cx3cr1(CreER-Eyfp/wt)Rosa26(DTA/wt) mice and CSF1 receptor inhibitor PLX3397 were used to deplete microglia. Primary microglia proliferation and migration assay were used for in vitro studies. Results We unexpectedly identified a subpopulation of microglia devoid of genetic modification, exhibiting higher Cx3cr1 and CX3CR1 expression than Cx3cr1(CreER-Eyfp/wt)Cre(+)Eyfp(+) microglia in Cx3cr1(CreER-Eyfp/wt) mouse brains, thus termed Cx3cr1(high)Cre(-)Eyfp(-) microglia. This subpopulation constituted less than 1% of all microglia under homeostatic conditions, but after Cre-driven DTA-mediated microglial depletion, Cx3cr1(high)Cre(-)Eyfp(-) microglia escaped depletion and proliferated extensively, eventually occupying one-third of the total microglial pool. We further demonstrated that the Cx3cr1(high)Cre(-)Eyfp(-) microglia had lost their genetic heterozygosity and become homozygous for wild-type Cx3cr1. Therefore, Cx3cr1(high)Cre(-)Eyfp(-) microglia are Cx3cr1(wt/wt)Cre(-)Eyfp(-). Finally, we demonstrated that CX3CL1-CX3CR1 signaling regulates microglial repopulation both in vivo and in vitro. Conclusions Our results raise a cautionary note regarding the use of Cx3cr1(CreER-Eyfp/wt) mouse strains, particularly when interpreting the results of fate mapping, and microglial depletion and repopulation studies.

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  • 17.
    Zyśk, Marlena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Naia, Luana
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Pavenius, Linnea
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden..
    Brismar, Hjalmar
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden.;Royal Inst Technol, Dept Appl Phys, Sci Life Lab, S-17165 Stockholm, Sweden..
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Ankarcrona, Maria
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 43Article in journal (Refereed)
    Abstract [en]

    Background: Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (A beta). However, in which way these A beta deposits influence their energy production remain unclear.

    Methods: The aim of the present study was to investigate how A beta pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils for 7 days and analyzed over time using different experimental approaches.

    Results: Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the A beta-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the A beta-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid beta-oxidation and glycolysis.

    Conclusions: Taken together, our data conclude that A beta pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

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