Cited by 351Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

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Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

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Reichenbach, Nicole, Delekate, Andrea, Plescher, Monika, Schmitt, Franziska, Krauss, Sybille, Blank, Nelli, Halle, Annett, Petzold, Gabor C·2019·EMBO Molecular Medicine

DOI 10.15252/emmm.201809665PMC PMC6365929

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Abstract

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression has remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD. Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD. We found that Stat3‐deficient APP/PS1 mice show decreased β‐amyloid levels and plaque burden. Plaque‐close microglia displayed a more complex morphology, internalized more β‐amyloid, and upregulated amyloid clearance pathways in Stat3‐deficient mice. Moreover, astrocyte‐specific Stat3‐deficient APP/PS1 mice showed decreased pro‐inflammatory cytokine activation and lower dystrophic neurite burden, and were largely protected from cerebral network imbalance. Finally, Stat3 deletion in astrocytes also strongly ameliorated spatial learning and memory decline in APP/PS1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP/PS1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3‐mediated astrogliosis as an important therapeutic target in AD.

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Authors: Reichenbach, N., Delekate, A., Plescher, M., Schmitt, F., Krauss, S., Blank, N., Halle, A., & Petzold, G. C.
Affiliations: German Center for Neurodegenerative Diseases (DE)
University Hospital Bonn (DE)
Corresponding author: Petzold, Gabor C
ORCID: Reichenbach, Nicole
Delekate, Andrea
Plescher, Monika
Schmitt, Franziska
Krauss, Sybille
Halle, Annett
Petzold, Gabor C
Venue: EMBO Molecular Medicine
Publisher: Springer Science and Business Media LLC
Published: 2019-01-07
Volume: 11
Issue: 2
ISSN: 1757-4676 (ISSN-L)
1757-4684
DOI: 10.15252/emmm.201809665
PMC: PMC6365929
OpenAlex: W2907017802
Cited by: 343
References: 42
Citations by year: 2026: 36 · 2025: 50 · 2024: 63 · 2023: 47 · 2022: 54 · 2021: 49 · 2020: 34 · 2019: 9
FWCI: 25.02
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: EMBO Molecular Medicine (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
DZNE Pub (submittedVersion, other-oa)
Funders: European Union (EU) Joint Program, Neurodegenerative Disease Research JPND (643417/DACAPO‐AD)
Alzheimer Forschung Initiative
Deutsches Zentrum für Neurodegenerative Erkrankungen
Deutsche Forschungsgemeinschaft (EXC 1023)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: STAT3, astrocyte activation, Alzheimer's disease, APP/PS1 mice, amyloid-beta, amyloid plaques, microglia, amyloid clearance, neuroinflammation, inflammatory cytokines, dystrophic neurites, spatial learning and memory, STAT3 inhibitor, therapeutic target
MeSH terms: Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Humans, Mice, Knockout, Cell Proliferation, STAT3 Transcription Factor, Mice, Gene Knockout Techniques

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Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

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