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 1

CXCR3 deficiency leads to a strong reduction of Aβ deposition in APP/PS1 mice.

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CXCR3 deficiency leads to a strong reduction of Aβ deposition in APP/PS1...
(A) Brain sections of 8-month-old APP/PS1 and APP/PS1/Cxcr3–/– male mice were stained with ThioS to detect Aβ deposition. Scale bar: 500 μm. (B) Hippocampal and cortical regions were quantified. (C) ELISA measurement of Aβ1–40 and Aβ1–42 peptides documents a reduction in the insoluble brain fraction of APP/PS1/Cxcr3–/– mice. (D) At 5 months (5 mo), no significant changes in the composition of both soluble peptides were observed in APP/PS1/Cxcr3–/– compared with APP/PS1 mice. At 8 months, both Aβ peptides are significantly reduced in APP/PS1/Cxcr3–/– mice. (E) A scatter plot of soluble Aβ1–40/1–42 composition in 5- and 8-month-old APP/PS1 and APP/PS1/Cxcr3–/– mice is shown. Immunoblot analysis using a holo-APP antibody (CT15) indicates no effect of CXCR3 deficiency on APP processing in APP/PS1 mice at 5 months. (F) Densitometric analysis of holo-APP, α-CTFs, and β-CTFs after normalization to α-tubulin. (G) Unaltered Aβ1–40 and Aβ1–42 secretion of primary cortical APP/PS1/Cxcr3–/– neurons compared with the APP/PS1 genotype. n = 4 cultures of both genotypes. (H) Cxcr3 RNA detection by qPCR confirms the lack of CXCR3 in primary cultured neurons, astrocytes, and microglia. (A–F) Data are shown as mean ± SEM, n = 5–8 mice per group. (H) Data are shown as mean ± SEM, n = 3–5 primary cultures in each group. *P < 0.05; **P < 0.005; ***P < 0.001.