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  • 1.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Biomedicum, Dept Neurosci, Lab B0851, Solnavägen 9, S-17177 Stockholm, Sweden; Univ Urbino, Sect Morphol Physiol & Environm Biol, Dept Biomol Sci, Campus Sci Enrico Mattei, Via Ca Le Suore 2, I-61029 Urbino, Italy; Observ Cubano Neurociencias, Grp Bohio Estudio, Zayas 50, Yaguajay 62100, Cuba.
    Ambrogini, Patrizia
    Univ Urbino, Sect Morphol Physiol & Environm Biol, Dept Biomol Sci, Campus Sci Enrico Mattei,Via Ca Le Suore 2, I-61029 Urbino, Italy.
    Chruscicka, Barbara
    Univ Coll Cork, APC Microbiome Ireland, Cork T12K8AF, Ireland; Jagiellonian Univ, Malopolska Ctr Biotechnol, PL-30252 Krakow, Poland.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Crespo-Ramirez, Minerva
    Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Mexico City 04510, DF, Mexico.
    Hernandez-Mondragon, Juan C.
    Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Mexico City 04510, DF, Mexico.
    Perez de la Mora, Miguel
    Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Mexico City 04510, DF, Mexico.
    Schellekens, Harriët
    Univ Coll Cork, Dept Anat & Neurosci, Cork T12K8AF, Ireland.
    Fuxe, Kjell
    Karolinska Inst, Biomedicum, Dept Neurosci, Lab B0851, Solnavägen 9, S-17177 Stockholm, Sweden.
    The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 4, article id 1927Article, review/survey (Refereed)
    Abstract [en]

    Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.

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  • 2.
    Dentoni, Giacomo
    et al.
    Department of Neurobiology, Karolinska Institutet, Care Science and Society, Division of Neurogeriatrics, Stockholm, Sweden.
    Naia, Luana
    Department of Neurobiology, Karolinska Institutet, Care Science and Society, Division of Neurogeriatrics, Stockholm, Sweden.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Leal, Nuno Santos
    Department of Neurobiology, Karolinska Institutet, Care Science and Society, Division of Neurogeriatrics, Stockholm, Sweden.
    Nilsson, Per
    Department of Neurobiology, Karolinska Institutet, Care Science and Society, Division of Neurogeriatrics, 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
    Department of Neurobiology, Karolinska Institutet, Care Science and Society, Division of Neurogeriatrics, Stockholm, Sweden.
    Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease2022In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 90, no 2, p. 565-583Article in journal (Refereed)
    Abstract [en]

    Background:

    Alzheimer’s disease (AD) research has relied on mouse models overexpressing human mutant A βPP; however, newer generation knock-in models allow for physiological expression of amyloid-β protein precursor (AβPP) containing familial AD mutations where murine AβPP is edited with a humanized amyloid-β (Aβ) sequence. The AppNL-F mouse model has shown substantial similarities to AD brains developing late onset cognitive impairment.

    Objective:

    In this study, we aimed to characterize mature primary cortical neurons derived from homozygous AppNL-F embryos, especially to identify early mitochondrial alterations in this model.

    Methods:

    Primary cultures of AppNL-F neurons kept in culture for 12–15 days were used to measure Aβ levels, secretase activity, mitochondrial functions, mitochondrial-ER contacts, synaptic function, and cell death.

    Results:

    We detected higher levels of Aβ42 released from AppNL-F neurons as compared to wild-type neurons. AppNL-F neurons, also displayed an increased Aβ42/Aβ40 ratio, similar to adult AppNL-F mouse brain. Interestingly, we found an upregulation in mitochondrial oxygen consumption with concomitant downregulation in glycolytic reserve. Furthermore, AppNL-F neurons were more susceptible to cell death triggered by mitochondrial electron transport chain inhibition. Juxtaposition between ER and mitochondria was found to be substantially upregulated, which may account for upregulated mitochondrial-derived ATP production. However, anterograde mitochondrial movement was severely impaired in this model along with loss in synaptic vesicle protein and impairment in pre- and post-synaptic function.

    Conclusion:

    We show that widespread mitochondrial alterations can be detected in AppNL-F neurons in vitro, where amyloid plaque deposition does not occur, suggesting soluble and oligomeric Aβ-species being responsible for these alterations.

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  • 3.
    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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  • 4.
    Mothes, Tobias
    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.
    Konstantinidis, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eltom, Khalid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Streubel-Gallasch, Linn
    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. Univ Hlth Network, Krembil Brain Inst, Toronto, ON, Canada; Univ Toronto, Dept Med, Toronto, ON, Canada.
    Rostami, Jinar
    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.
    Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology2023In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed)
    Abstract [en]

    Tau deposits in astrocytes are frequently found in Alzheimer's disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

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  • 5.
    Vazquez-Juarez, Erika
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Srivastava, Ipsit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden..
    The effect of ketamine on synaptic mistuning induced by impaired glutamate reuptake2023In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, no 13, p. 1859-1868Article in journal (Refereed)
    Abstract [en]

    Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one contributing factor. Synaptic tuning occurs through several diverging and converging forms of plasticity. By recording evoked field postsynaptic potentials in the CA1 area in hippocampal slices, we found that inhibiting glutamate transporters using DL-TBOA causes retuning of synaptic transmission, resulting in a new steady state with reduced synaptic strength and a lower threshold for inducing long-term synaptic potentiation (LTP). Moreover, a similar reduced threshold for LTP was observed in a rat model of depression with decreased levels of glutamate transporters. Most importantly, we found that the antidepressant ketamine counteracts the effects of increased glutamate on the various steps involved in synaptic retuning. We, therefore, propose that ketamine's mechanism of action as an antidepressant is to restore adequate synaptic tuning.

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  • 6.
    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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