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Zyśk, M., Beretta, C., Naia, L., Dakhel, A., Pavenius, L., Brismar, H., . . . Erlandsson, A. (2023). Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism. Journal of Neuroinflammation, 20, Article ID 43.
Open this publication in new window or tab >>Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
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2023 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 43Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Alzheimer's disease, Glia, Lipid droplets, Mitochondria dynamics, DRP-1
National Category
Neurology Cell Biology
Identifiers
urn:nbn:se:uu:diva-498551 (URN)10.1186/s12974-023-02722-z (DOI)000935963900001 ()36803838 (PubMedID)
Funder
Swedish Research Council, 2021-02563Uppsala UniversityAlzheimerfonden, AF-968209Åhlén-stiftelsen, 213021The Swedish Brain Foundation, FO2021-0174Stiftelsen Gamla Tjänarinnor, 2021-01171O.E. och Edla Johanssons vetenskapliga stiftelseOlle Engkvists stiftelse, 215-0399Bertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes Stiftelse
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2023-03-17 Created: 2023-03-17 Last updated: 2024-03-26Bibliographically approved
Mothes, T., Portal, B., Konstantinidis, E., Eltom, K., Libard, S., Streubel-Gallasch, L., . . . Erlandsson, A. (2023). Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology. Acta neuropathologica communications, 11(1), Article ID 97.
Open this publication in new window or tab >>Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology
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2023 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Alzheimer's disease, Tau, Astrocytes, Neurons, Cell-to-cell spreading, hiPSCs
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-506917 (URN)10.1186/s40478-023-01589-8 (DOI)001007228100001 ()37330529 (PubMedID)
Funder
Uppsala UniversitySwedish Research Council, 2021–02563Alzheimerfonden, AF‑968209Åhlén-stiftelsen, 213021The Swedish Brain Foundation, FO2021‑0174Stiftelsen Gamla Tjänarinnor, 2021–01171O.E. och Edla Johanssons vetenskapliga stiftelseOlle Engkvists stiftelse, 215–0399Bertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes Stiftelse
Available from: 2023-06-30 Created: 2023-06-30 Last updated: 2024-02-23Bibliographically approved
Konstantinidis, E., Portal, B., Mothes, T. J., Beretta, C., Lindskog, M. & Erlandsson, A. (2023). Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function. Journal of Neuroinflammation, 20(1), Article ID 3.
Open this publication in new window or tab >>Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function
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2023 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, no 1, article id 3Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-492283 (URN)10.1186/s12974-022-02687-5 (DOI)000906707700001 ()36593462 (PubMedID)
Funder
Swedish Research Council, 2021-02563Alzheimerfonden, AF-968209Åhlén-stiftelsen, 213021The Swedish Brain Foundation, FO2021-0174O.E. och Edla Johanssons vetenskapliga stiftelse, 2021Olle Engkvists stiftelse, 215-0399Gun och Bertil Stohnes Stiftelse, 2021Uppsala UniversityBertil and Ebon Norlin Foundation for Medical Research, 2021
Available from: 2023-01-03 Created: 2023-01-03 Last updated: 2023-01-19Bibliographically approved
Vazquez-Juarez, E., Srivastava, I. & Lindskog, M. (2023). The effect of ketamine on synaptic mistuning induced by impaired glutamate reuptake. Neuropsychopharmacology, 48(13), 1859-1868
Open this publication in new window or tab >>The effect of ketamine on synaptic mistuning induced by impaired glutamate reuptake
2023 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, no 13, p. 1859-1868Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-519653 (URN)10.1038/s41386-023-01617-0 (DOI)001002967400001 ()37301901 (PubMedID)
Available from: 2024-01-09 Created: 2024-01-09 Last updated: 2024-01-09Bibliographically approved
Dentoni, G., Naia, L., Portal, B., Leal, N. S., Nilsson, P., Lindskog, M. & Ankarcrona, M. (2022). Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 90(2), 565-583
Open this publication in new window or tab >>Mitochondrial Alterations in Neurons Derived from the Murine AppNL-F Knock-In Model of Alzheimer's Disease
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2022 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 90, no 2, p. 565-583Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
IOS Press, 2022
Keywords
Alzheimer’s disease, AppNL-F knock-in mice, mitochondria, mitochondria-ER contact sites, synapses
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-486749 (URN)10.3233/jad-220383 (DOI)000886925300010 ()36155507 (PubMedID)
Funder
EU, Horizon 2020, 676.144The Swedish Brain Foundation, FO2019–0145Swedish Research Council, 2018–03102Alzheimerfonden, AF-940133Stiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseKarolinska Institute, StratNeuro
Available from: 2022-10-16 Created: 2022-10-16 Last updated: 2022-12-19Bibliographically approved
Borroto-Escuela, D. O., Ambrogini, P., Chruscicka, B., Lindskog, M., Crespo-Ramirez, M., Hernandez-Mondragon, J. C., . . . Fuxe, K. (2021). The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects. International Journal of Molecular Sciences, 22(4), Article ID 1927.
Open this publication in new window or tab >>The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 4, article id 1927Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
G protein-coupled receptors, heteroreceptor complexes, serotonin receptor, oligomerization, oxytocin receptor, depression
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-441133 (URN)10.3390/ijms22041927 (DOI)000623875400001 ()33672070 (PubMedID)
Funder
Swedish Research Council, 62X-00715-50-3Stiftelsen Olle Engkvist ByggmästareThe Swedish Brain Foundation, F02018-0286The Swedish Brain Foundation, F02019-0296The Karolinska Institutet's Research Foundation
Available from: 2021-05-25 Created: 2021-05-25 Last updated: 2024-01-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4178-2825

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