TY  - JOUR
AU  - Reichenbach, Nicole
AU  - Delekate, Andrea
AU  - Plescher, Monika
AU  - Schmitt, Franziska
AU  - Krauß, Sybille
AU  - Blank, Nelli
AU  - Halle, Annett
AU  - Petzold, Gabor C
TI  - Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model.
JO  - EMBO molecular medicine
VL  - 11
IS  - 2
SN  - 1757-4676
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2020-06804
SP  - e9665
PY  - 2019
AB  - 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.
KW  - Alzheimer Disease: pathology
KW  - Animals
KW  - Astrocytes: pathology
KW  - Cell Proliferation
KW  - Disease Models, Animal
KW  - Gene Knockout Techniques
KW  - Humans
KW  - Mice
KW  - Mice, Knockout
KW  - STAT3 Transcription Factor: analysis
KW  - STAT3 Transcription Factor: deficiency
KW  - STAT3 Transcription Factor (NLM Chemicals)
KW  - STAT3 protein, human (NLM Chemicals)
KW  - Stat3 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30617153
C2  - pmc:PMC6365929
DO  - DOI:10.15252/emmm.201809665
UR  - https://pub.dzne.de/record/140482
ER  -