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PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease
Open accessAbstract
Alzheimer's disease (AD) is a common neurodegenerative disorder and the leading cause of cognitive impairment. Due to insufficient understanding of the disease mechanisms, there are no efficient therapies for AD. Most studies have focused on neuronal cells, but astrocytes have also been suggested to contribute to AD pathology. We describe here the generation of functional astrocytes from induced pluripotent stem cells (iPSCs) derived from AD patients with PSEN1 ΔE9 mutation, as well as healthy and gene-corrected isogenic controls. AD astrocytes manifest hallmarks of disease pathology, including increased β-amyloid production, altered cytokine release, and dysregulated Ca 2+ homeostasis. Furthermore, due to altered metabolism, AD astrocytes show increased oxidative stress and reduced lactate secretion, as well as compromised neuronal supportive function, as evidenced by altering Ca 2+ transients in healthy neurons. Our results reveal an important role for astrocytes in AD pathology and highlight the strength of iPSC-derived models for brain diseases.
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“In our study, the continuum of GFAF/S100B-positive cells, ranging from roundish/polarized ones to highly arborized cells, agrees with previous studies [27,28].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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“Ast-AD revealed fewer GFAP-positive cells than S100B-positive ones, with low HMGB1 and IL-10 and elevated IL-6 and C/EBPα gene levels, already pointing to some altered properties [27,72,120].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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“Characterization for genetic stability and pluripotency markers of these iPSCs was previously documented in studies using iPSC differentiation into astrocytes and microglia for the screening of AD-associated glial aberrancies [26,27].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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“The cells displayed heterogeneous shapes, but mostly the stellate morphology characteristic of glial cells [27] (Figure 6B), and the astrocyte-associated GFAP and S100B markers (Figure 6C)”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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“some authors have stimulated astrocytes with TNF-α and IL-1β to make their pathological profiles more visible [27].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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“because astrocytes are known to contribute to neuroinflammation when reactive”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [27]
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Metadata
- Authors
- Oksanen, M., Petersen, A. J., Naumenko, N., Puttonen, K., Lehtonen, Š., Gubert Olivé, M., Shakirzyanova, A., Leskelä, S., Sarajärvi, T., Viitanen, M., Rinne, J. O., Hiltunen, M., Haapasalo, A., Giniatullin, R., Tavi, P., Zhang, S.-C., Kanninen, K. M., Hämäläinen, R. H., & Koistinaho, J.
- Affiliations
- University of Eastern Finland (FI)
- University of Wisconsin–Madison (US)
- Karolinska University Hospital (SE)
- University of Turku (FI)
- University of Wisconsin System (US)
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 9
- Issue
- 6
- Pages
- 1885-1897
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC5785689
- OpenAlex
- W2768957663
- Cited by
- 332
- References
- 65
- Citations by year
- 2026: 27 · 2025: 22 · 2024: 46 · 2023: 37 · 2022: 49 · 2021: 41 · 2020: 50 · 2019: 43 · 2018: 17
- FWCI
- 22.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by-nc-nd)
- UTUPub (University of Turku) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Itä-Suomen Yliopisto
- Academy of Finland
- Tekes
- Emil Aaltosen Säätiö
- Sigrid Juséliuksen Säätiö
- Horizon 2020 (643417)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, astrocytes, induced pluripotent stem cells, iPSC-derived astrocytes, amyloid-beta production, cytokine production, calcium homeostasis, oxidative stress, lactate secretion, disease modeling, isogenic controls
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Calcium, Gene Expression Regulation, Humans, Mitochondria, Neurons, Amyloid beta-Peptides, Oxidative Stress, Lactic Acid, Presenilin-1, Induced Pluripotent Stem Cells
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