Journal Article

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

Plescher, Monika, Reichenbach, Nicole, Krauss, Sybille, Blank, Nelli, Petzold, Gabor C, Delekate, Andrea, Halle, Annett, Schmitt, Franziska

2019

Overview

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. Synopsis Modulation of Stat3‐mediated reactive astrogliosis in an Alzheimer's disease mouse model attenuates pathology, enhances amyloid clearance and protects from cognitive decline. These effects are recapitulated in mice treated with a pharmacological Stat3 inhibitor. Generation of a Stat3 (a canonical mediator of reactive astrogliosis) deletion specifically in astrocytes in a mouse model of Alzheimer's disease (AD). Stat3 depletion resulted in strongly attenuated AD‐related pathology, better microglial amyloid clearance, normalization of cerebral network function and a preservation of learning and memory. Protection was recapitulated in AD model mice treated with a pharmacological Stat3 inhibitor, implicating modulation of reactive astrogliosis as a novel treatment target in AD. Graphical Abstract Modulation of Stat3‐mediated reactive astrogliosis in an Alzheimer's disease mouse model attenuates pathology, enhances amyloid clearance and protects from cognitive decline. These effects are recapitulated in mice treated with a pharmacological Stat3 inhibitor.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Alzheimer Disease - pathology / Alzheimer's disease / Animals / Astrocytes / Astrocytes - pathology / astrogliosis / Cell Proliferation / Cognitive ability / Disease Models, Animal / EMBO19 / EMBO27 / EMBO28 / Gene Knockout Techniques / glia / Gliosis / Humans / Inflammation / Mice / Mice, Knockout / Microglia / Neurodegenerative diseases / Pathology / Presenilin 1 / Preservation / Research Article / Spatial discrimination learning / Spatial memory / Stat3 / Stat3 protein / STAT3 Transcription Factor - analysis / STAT3 Transcription Factor - deficiency / Therapeutic applications