Open AccessInhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model
Author(s) -
Reichenbach Nicole,
Delekate Andrea,
Plescher Monika,
Schmitt Franziska,
Krauss Sybille,
Blank Nelli,
Halle Annett,
Petzold Gabor C
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809665
Subject(s) - astrogliosis , stat3 , microglia , gliosis , stat protein , neurite , presenilin , conditional gene knockout , senile plaques , alzheimer's disease , biology , neuroscience , medicine , immunology , cancer research , microbiology and biotechnology , pathology , inflammation , signal transduction , central nervous system , disease , biochemistry , gene , in vitro , phenotype
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 / PS 1 model of AD . We found that Stat3‐deficient APP / PS 1 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 / PS 1 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 / PS 1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP / PS 1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3‐mediated astrogliosis as an important therapeutic target in AD .