STAT3 inhibition protects against neuroinflammation and BACE1 upregulation induced by systemic inflammation

Immunol Lett. 2020 Dec:228:129-134. doi: 10.1016/j.imlet.2020.10.004. Epub 2020 Oct 21.

Abstract

Abnormal activation of the transcriptional factor STAT3 (signal transducer and activator of transcription 3) was recently associated with Alzheimer Disease (AD). STAT3 phosphorylation is critical for cytokine secretion linked to neuroinflammation. Moreover, STAT3 may act as a transcriptional regulator of BACE1 (β-APP cleaving enzyme-1), the key enzyme in amyloid β (Aβ) production. We have previously shown that neuroinflammation and increased brain BACE1 levels triggered by LPS-induced systemic inflammation in wild-type mice are associated with an enhanced STAT3 activation. Using this LPS model, the goal of this study was to investigate if a STAT3 inhibitor administration could be protective against neuroinflammation and abnormal BACE1 regulation. Our results show that intraperitoneal injection of Stattic, a molecule that selectively inhibits the activation of STAT3, decreases LPS-induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduced brain levels of cytokines IL-6, IL-1β and TNF-α triggered by LPS systemic administration. A significant reduction of BACE1 levels was observed in the hippocampus of mice treated with LPS and Stattic compared to those exposed to LPS alone. Taking together, our results show that Stattic can protect hippocampus against two pathological hallmarks of AD, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.

Keywords: BACE1; LPS; Microglial activation; Neuroinflammation; STAT3; Stattic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Aspartic Acid Endopeptidases / metabolism*
  • Cyclic S-Oxides / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Hippocampus / drug effects*
  • Hippocampus / enzymology
  • Hippocampus / immunology
  • Inflammation / chemically induced
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / immunology
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides
  • Male
  • Mice, Inbred C57BL
  • Microglia / drug effects*
  • Microglia / enzymology
  • Microglia / immunology
  • Neuroimmunomodulation / drug effects*
  • Phosphorylation
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • Anti-Inflammatory Agents
  • Cyclic S-Oxides
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • stattic
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse