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Gallasch, Linn
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Publications (6 of 6) Show all publications
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., Molisak, A., Perrin, F., Streubel-Gallasch, L., Fayad, S., Kim, D. Y., . . . Ingelsson, M. (2022). CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation. Molecular Therapy Nucleic Acids, 28, 450-461
Open this publication in new window or tab >>CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation
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2022 (English)In: Molecular Therapy Nucleic Acids, E-ISSN 2162-2531, Vol. 28, p. 450-461Article in journal (Refereed) Published
Abstract [en]

Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) peptide that deposits as plaques in the Alzheimer’s disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aβ42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aβ42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.

Keywords
MT, RNA/DNA editing, Alzheimer’s disease, presenilin 1, amyloid-β, fibroblasts, CRISPR-Cas9, gene editing, protein conformation, off-target effects
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics Neurology
Identifiers
urn:nbn:se:uu:diva-475572 (URN)10.1016/j.omtn.2022.03.022 (DOI)000795090300005 ()35505961 (PubMedID)
Funder
Swedish Research Council, 2018-03075Swedish Research Council, 2021-02793AlzheimerfondenThe Swedish Brain FoundationÅhlén-stiftelsenStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseNIH (National Institutes of Health), R35 GM118158German Research Foundation (DFG), 417577129NIH (National Institutes of Health), AG044486NIH (National Institutes of Health), AG015379
Note

Title in Web of Science: CRISPR-Cas9 treatment partially restores amyloid-beta 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation

Available from: 2022-06-03 Created: 2022-06-03 Last updated: 2023-11-03Bibliographically approved
Streubel-Gallasch, L., Giusti, V., Sandre, M., Tessari, I., Plotegher, N., Giusto, E., . . . Civiero, L. (2021). Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance. Molecular Neurobiology, 58(7), 3119-3140
Open this publication in new window or tab >>Parkinson's Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance
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2021 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 58, no 7, p. 3119-3140Article in journal (Refereed) Published
Abstract [en]

Parkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (alpha-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects alpha-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in alpha-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary alpha-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated alpha-syn for 24 h and analyzed directly after the alpha-syn pulse or 6 days later. To elucidate the impact of LRRK2 on alpha-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar alpha-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of alpha-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular alpha-syn aggregates through an AnxA2-dependent mechanism.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
Keywords
Parkinson's disease, alpha-Synuclein, LRRK2, Astrocytes, Glia, Neurodegeneration
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-454347 (URN)10.1007/s12035-021-02327-8 (DOI)000621275500002 ()33629273 (PubMedID)
Funder
Swedish Research Council
Available from: 2021-09-29 Created: 2021-09-29 Last updated: 2024-01-15Bibliographically approved
Streubel-Gallasch, L., Zyśk, M., Beretta, C. & Erlandsson, A. (2021). Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy. Scientific Reports, 11(1), Article ID 22982.
Open this publication in new window or tab >>Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy
2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22982Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer’s disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid β (Aβ) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aβ42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aβ exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aβ deposits and helps to advance the understanding of geriatric TBI on the cellular level.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-461726 (URN)10.1038/s41598-021-02371-3 (DOI)000722925300054 ()34837024 (PubMedID)
Funder
Swedish Research Council
Available from: 2022-02-04 Created: 2022-02-04 Last updated: 2024-01-15Bibliographically approved
Beretta, C., Nikitidou, E., Gallasch, L., Ingelsson, M., Sehlin, D. & Erlandsson, A. (2020). Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons. Scientific Reports, 10, Article ID 19656.
Open this publication in new window or tab >>Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, article id 19656Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.

Place, publisher, year, edition, pages
NATURE RESEARCH, 2020
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-428933 (URN)10.1038/s41598-020-72355-2 (DOI)000595255700049 ()33184307 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla Tjänarinnor
Available from: 2020-12-18 Created: 2020-12-18 Last updated: 2024-03-26Bibliographically approved
Söllvander, S., Nikitidou, E., Gallasch, L., Zysk, M., Söderberg, L., Sehlin, D., . . . Erlandsson, A. (2018). The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta-induced cell death. Journal of Neuroinflammation, 15, Article ID 98.
Open this publication in new window or tab >>The A beta protofibril selective antibody mAb158 prevents accumulation of A beta in astrocytes and rescues neurons from A beta-induced cell death
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2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 98Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Alzheimer's disease, Amyloid-beta, Antibody, Clearance, Astrocyte, Neuron
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-354346 (URN)10.1186/s12974-018-1134-4 (DOI)000428573400001 ()29592816 (PubMedID)
Funder
Swedish Research Council, 2012-2172Magnus Bergvall Foundation
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2022-01-29Bibliographically approved
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