CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model
Marius Krauthausen, … , Michael T. Heneka, Marcus Müller
Marius Krauthausen, … , Michael T. Heneka, Marcus Müller
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):365-378. https://doi.org/10.1172/JCI66771.
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Research Article Neuroscience

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Abstract

Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer’s disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/PSI animals, plaque burden and Aβ levels were strongly reduced in CXCR3-deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of Aβ. Application of a CXCR3 antagonist increased microglial Aβ phagocytosis, which was associated with reduced TNF-α secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD.

Authors

Marius Krauthausen, Markus P. Kummer, Julian Zimmermann, Elisabet Reyes-Irisarri, Dick Terwel, Bruno Bulic, Michael T. Heneka, Marcus Müller

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Figure 5

CXCR3 deficiency and CXCR3 antagonism enhance microglial phagocytosis of FAM-Aβ and reduce the production of TNF-α in vitro.

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CXCR3 deficiency and CXCR3 antagonism enhance microglial phagocytosis of...
(A) Primary WT and Cxcr3–/– microglia (CD68, red signal) were incubated with or without 0.7 μM FAM-Aβ for 1 hour. Scale bar: 20 μm. (B) A phagocytosis assay revealed a significant increase of FAM-Aβ uptake in Cxcr3–/– compared with WT microglia. mCXCL9 and mCXCL10 (each 250 ng/ml) treatment of WT and Cxcr3–/– microglia diminished phagocytosis in WT but not in Cxcr3–/– cells. (C) Reduced TNF-α concentration in the cell supernatants of Aβ-stimulated Cxcr3–/– microglia cultures. (D) Functional blocking of CXCR3 with an antagonist enhances microglial phagocytosis to levels equal to those found in CXCR3-deficient microglia (CXCR3 antagonist ≥ 100 nM). (E) Analysis of the TNF-α level in CXCR3 antagonist–treated WT microglia exhibits a reduction of TNF-α secretion below WT control level when stimulated with Aβ. Data are shown as mean ± SEM from 3 to 5 individual experiments; *P < 0.05; **P < 0.01; ***P < 0.001 (1-way ANOVA, Dunn’s post hoc test).