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Pagnon de la Vega, M., Syvänen, S., Giedraitis, V., Hooley, M., Konstantinidis, E., Meier, S. R., . . . Sehlin, D. (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications, 12(1), Article ID 22.
Open this publication in new window or tab >>Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 22Article in journal (Refereed) Published
Abstract [en]

Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Alzheimer's disease (AD), Amyloid precursor protein (APP), Amyloid-beta (A beta), PET imaging, Microglia, Astrocytes, Immunotherapy
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:uu:diva-523728 (URN)10.1186/s40478-024-01734-x (DOI)001158145500001 ()38317196 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationUppsala UniversitySwedish Research Council, 2016‑02120Swedish Research Council, 2021‑01083Swedish Research Council, 2021‑03524AlzheimerfondenThe Swedish Brain FoundationTorsten Söderbergs stiftelseÅhlén-stiftelsenMagnus Bergvall FoundationStiftelsen Gamla TjänarinnorGun och Bertil Stohnes StiftelseKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseStiftelsen Sigurd och Elsa Goljes minne
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2024-02-26 Created: 2024-02-26 Last updated: 2024-02-26Bibliographically approved
Beretta, C., Svensson, E., Dakhel, A., Zyśk, M., Hanrieder, J., Sehlin, D., . . . Erlandsson, A. (2024). Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms. Molecular and Cellular Neuroscience, 128, Article ID 103916.
Open this publication in new window or tab >>Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
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2024 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 128, article id 103916Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Alzheimer's disease, Amyloid β, Astrocytes, Aggregate
National Category
Other Medical Sciences not elsewhere specified Other Biological Topics Neurosciences
Identifiers
urn:nbn:se:uu:diva-525108 (URN)10.1016/j.mcn.2024.103916 (DOI)001175074700001 ()
Funder
Uppsala UniversitySwedish Research Council, 2021-02563Alzheimerfonden, AF-980656Åhlén-stiftelsen, 223037The Swedish Brain Foundation, FO2022-0083Stiftelsen 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: 2024-03-15 Created: 2024-03-15 Last updated: 2024-04-09Bibliographically approved
Eltom, K., Mothes, T., Libard, S., Ingelsson, M. & Erlandsson, A. (2024). Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment. Acta neuropathologica communications, 12(1), Article ID 34.
Open this publication in new window or tab >>Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Alzheimer’s disease; tau; astrocytes; brain-derived fibrils; inflammation; neurons
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-523823 (URN)10.1186/s40478-024-01745-8 (DOI)001176894300001 ()38409026 (PubMedID)
Funder
Åhlén-stiftelsen, 233044The Swedish Brain Foundation, FO2022-0083Stiftelsen Gamla Tjänarinnor, 2021 − 01171O.E. och Edla Johanssons vetenskapliga stiftelseBertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes StiftelseSwedish Fund for Research Without Animal Experiments, F2022-0004Uppsala University
Available from: 2024-02-23 Created: 2024-02-23 Last updated: 2024-04-10Bibliographically approved
Brolin, E., Ingelsson, M., Bergström, J. & Erlandsson, A. (2023). Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms. Cellular and molecular neurobiology, 43(6), 3023-3035
Open this publication in new window or tab >>Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms
2023 (English)In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 43, no 6, p. 3023-3035Article in journal (Refereed) Published
Abstract [en]

Growing evidence indicates that the pathological alpha-synuclein (a-syn) aggregation in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) starts at the synapses. Physiologic a-syn is involved in regulating neurotransmitter release by binding to the SNARE complex protein VAMP-2 on synaptic vesicles. However, in which way the SNARE complex formation is affected by a-syn pathology remains unclear. In this study, primary cortical neurons were exposed to either a-syn monomers or preformed fibrils (PFFs) for different time points and the effect on SNARE protein distribution was analyzed with a novel proximity ligation assay (PLA). Short-term exposure to monomers or PFFs for 24 h increased the co-localization of VAMP-2 and syntaxin-1, but reduced the co-localization of SNAP-25 and syntaxin-1, indicating a direct effect of the added a-syn on SNARE protein distribution. Long-term exposure to a-syn PFFs for 7 d reduced VAMP-2 and SNAP-25 co-localization, although there was only a modest induction of ser129 phosphorylated (pS129) a-syn. Similarly, exposure to extracellular vesicles collected from astrocytes treated with a-syn PFFs for 7 d influenced VAMP-2 and SNAP-25 co-localization despite only low levels of pS129 a-syn being formed. Taken together, our results demonstrate that different a-syn proteoforms have the potential to alter the distribution of SNARE proteins at the synapse.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Alpha-synuclein, SNARE, Proximity ligation assay, Synapse, Primary neurons
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-511391 (URN)10.1007/s10571-023-01355-3 (DOI)000981547700001 ()37130995 (PubMedID)
Funder
Swedish Research Council, 202102563Parkinsonfonden, 1405/2022The Swedish Brain Foundation, FO2022-0062
Available from: 2023-09-22 Created: 2023-09-22 Last updated: 2023-09-22Bibliographically approved
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
Konstantinidis, E., Dakhel, A., Beretta, C. & Erlandsson, A. (2023). Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes. Molecular and Cellular Neuroscience, 125, Article ID 103839.
Open this publication in new window or tab >>Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes
2023 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 125, article id 103839Article in journal (Refereed) Published
Abstract [en]

Growing evidence indicates that astrocytes are tightly connected to Alzheimer's disease (AD) pathogenesis. However, the way in which astrocytes participate in AD initiation and progression remains to be clarified. Our previous data show that astrocytes engulf large amounts of aggregated amyloid-beta (A beta) but are unable to successfully degrade the material. In this study, we aimed to evaluate how intracellular A beta-accumulation affects the astrocytes over time. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta-fibrils and then cultured further for one week or ten weeks in A beta-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the media were screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy. Our data demonstrate that long-term astrocytes retained frequent A beta-inclusions that were enclosed within LAMP1-positive organelles and sustained markers associated with reactivity. Furthermore, A beta-accumulation resulted in endoplasmic reticulum and mitochondrial swelling, increased secretion of the cytokine CCL2/MCP-1 and formation of pathological lipid structures. Taken together, our results provide valuable information of how intracellular A beta-deposits affect astrocytes, and thereby contribute to the understanding of the role of astrocytes in AD progression.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Alzheimer?s disease, Amyloid beta, Astrocytes, Phagocytosis, Accumulation, Lysosomes, Neuroinflammation, Cytokines, Reactivity, Human iPSCs
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500295 (URN)10.1016/j.mcn.2023.103839 (DOI)000957221400001 ()36907531 (PubMedID)
Funder
Swedish Research Council, 2021-02563
Available from: 2023-04-25 Created: 2023-04-25 Last updated: 2023-04-25Bibliographically 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
Roshanbin, S., Aniszewska, A., Gumucio, A., Masliah, E., Erlandsson, A., Bergström, J., . . . Ekmark-Lewén, S. (2021). Age-related increase of alpha-synuclein oligomers is associated with motor disturbances in L61 transgenic mice. Neurobiology of Aging, 101, 207-220
Open this publication in new window or tab >>Age-related increase of alpha-synuclein oligomers is associated with motor disturbances in L61 transgenic mice
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2021 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 101, p. 207-220Article in journal (Refereed) Published
Abstract [en]

The pathogenesis of Parkinson's disease involves fibrillization and deposition of alpha-synuclein (alpha-syn) into Lewy bodies. Accumulating evidence suggests that alpha-syn oligomers are particularly neurotoxic. Transgenic (tg) mice overexpressing wild-type human alpha-syn under the Thy-1 promoter (L61) reproduce many Parkinson's disease features, but the pathogenetic relevance of alpha-syn oligomers in this mouse model has not been studied in detail. Here, we report an age progressive increase of alpha-syn oligomers in the brain of L61 tg mice. Interestingly, more profound motor symptoms were observed in animals with higher levels of membrane-bound oligomers. As this tg model is X-linked, we also performed subset analyses, indicating that both sexes display a similar age-related increase in alpha-syn oligomers. However, compared with females, males featured increased brain levels of oligomers from an earlier age, in addition to a more severe behavioral phenotype with hyperactivity and thigmotaxis in the open field test. Taken together, our data indicate that alpha-syn oligomers are central to the development of brain pathology and behavioral deficits in the L61 tg alpha-syn mouse model.

Place, publisher, year, edition, pages
ElsevierElsevier BV, 2021
Keywords
Parkinson's disease, Dementia with Lewy bodies, Alpha-synuclein, Transgenic mice, Sex differences, Aggregation, Oligomers, Thy-1, Age progression
National Category
Neurology Geriatrics
Identifiers
urn:nbn:se:uu:diva-446199 (URN)10.1016/j.neurobiolaging.2021.01.010 (DOI)000649652300021 ()33639338 (PubMedID)
Funder
Swedish Research Council, MI:2018-03075
Note

Joint first authors: Sahar Roshanbin and Agata Aniszewska

Available from: 2021-06-22 Created: 2021-06-22 Last updated: 2024-01-15Bibliographically approved
Projects
The role of astrocytes in development and progression of Alzheimer’s disease [2015-02671_VR]; Uppsala UniversityThe involvement of astrocytes in the progression of Alzheimer’s disease [2018-02659_VR]; Uppsala UniversityThe impact of astrocytes on Alzheimer’s disease progression [2021-02563_VR]; Uppsala University; Publications
Beretta, C., Svensson, E., Dakhel, A., Zyśk, M., Hanrieder, J., Sehlin, D., . . . Erlandsson, A. (2024). Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms. Molecular and Cellular Neuroscience, 128, Article ID 103916. Eltom, K., Mothes, T., Libard, S., Ingelsson, M. & Erlandsson, A. (2024). Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment. Acta neuropathologica communications, 12(1), Article ID 34.
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7292-1608

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