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 6

CXCR3 deficiency increases the microglial Aβ uptake in the APP/PS1 model and after intracerebral fAβ injection.

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CXCR3 deficiency increases the microglial Aβ uptake in the APP/PS1 model...
(A) Representative micrographs of microglia (Iba1) and Aβ (IC16) stainings together with methoxy-XO4–labeled Aβ in APP/PS1 and APP/PS1/Cxcr3–/– mice. Scale bar: 50 μm. (B) Using flow cytometry, Aβ uptake of CD11b+CD45+ microglia was found enhanced in APP/PS1/Cxcr3–/– animals compared with APP/PS1 animals (MFI). The percentage of methoxy-XO4+ microglia was slightly increased by CXCR3 deficiency. (C) Cxcr3–/– and WT mice were injected with fAβ, and brain sections were stained for IBA1/Aβ. Scale bar: 20 μm. (D) Quantification of IBA1+ microglia cells within the fAβ application center showed a higher number in WT than in Cxcr3–/– mice. (E) Large CD68+ lysosomes (red) containing Aβ immunoreactive content (green) were detected in Cxcr3–/– rather than in WT mice (arrowheads). Scale bars: 20 μm; 10 μm (insets). (F) Fluorescence intensities for CD68 (red stain and line) and Aβ (green stain and line) are shown next to the corresponding RGB image (simplified dimensioning arrow, distance 0-1 = 80 μm). RGB intensity profile localizes peak Aβ (green) intermediate to peak CD68 (red) fluorescence intensity. (G) CD68+ lysosomal content in Cxcr3–/– mice exhibits an increase in Aβ compared with WT mice. (H) A larger lysosomal perimeter was found in Cxcr3–/– microglia compared with WT. Data are shown as mean ± SEM, n = 5 mice per group. *P < 0.05; **P < 0.005; ***P < 0.001.