Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model
Open accessAbstract
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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Manipulation of reactive astrocytes has resulted in improved outcomes, worse outcomes, and no change in mouse models of AD and MS.
“For example, the manipulation of reactive astrocytes has resulted in improved outcomes38,42,43, worse35 outcomes, and no change44 in mouse models of AD and MS40,45,46.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [43]
Blocking astrocyte reactivity has positive effects on AD pathology.
“On the other hand, blocking astrocyte reactivity has demonstrated positive effects on pathology (Ceyzeriat et al., 2018; Reichenbach et al., 2019).”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Reichenbach et al., 2019
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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
- Venue
- EMBO Molecular Medicine
- Published
- 2019-01-07
- Volume
- 11
- Issue
- 2
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- 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
- 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
- Health Sciences › Medicine › Physiology › 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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