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Interleukin-10 deficiency exacerbates inflammation-induced tau pathology

Authors
  • Weston, Lea L.1
  • Jiang, Shanya1
  • Chisholm, Devon1
  • Jantzie, Lauren L.2
  • Bhaskar, Kiran1, 3
  • 1 University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM, 87131, USA , Albuquerque (United States)
  • 2 Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA , Baltimore (United States)
  • 3 University of New Mexico, 1 University of New Mexico, Albuquerque, NM, 87131, USA , Albuquerque (United States)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jul 18, 2021
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12974-021-02211-1
Source
Springer Nature
Keywords
Disciplines
  • Research
License
Green

Abstract

BackgroundThe presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies. However, the role of inflammation and anti-inflammatory interventions in tauopathies is unclear. Our goal was to determine if removing anti-inflammatory interleukin-10 (IL-10) during an acute inflammatory challenge has any effect on neuronal tau pathology.MethodsWe induce systemic inflammation in Il10-deficient (Il10−/−) versus Il10+/+ (Non-Tg) control mice using a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to examine microglial activation and abnormal hyperphosphorylation of endogenous mouse tau protein. Tau phosphorylation was quantified by Western blotting and immunohistochemistry. Microglial morphology was quantified by skeleton analysis. Cytokine expression was determined by multiplex electro chemiluminescent immunoassay (MECI) from Meso Scale Discovery (MSD).ResultsOur findings show that genetic deletion of Il10 promotes enhanced neuroinflammation and tau phosphorylation. First, LPS-induced tau hyperphosphorylation was significantly increased in Il10−/− mice compared to controls. Second, LPS-treated Il10−/− mice showed signs of neurodegeneration. Third, LPS-treated Il10−/− mice showed robust IL-6 upregulation and direct treatment of primary neurons with IL-6 resulted in tau hyperphosphorylation on Ser396/Ser404 site.ConclusionsThese data support that loss of IL-10 activates microglia, enhances IL-6, and leads to hyperphosphorylation of tau on AD-relevant epitopes in response to acute systemic inflammation.

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