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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 Article has an altmetric score of 50

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

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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 4

Effect of fibrillar fAβ on the induction of microglial and astrocytic TNF-α and CXCL10 secretion.

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Effect of fibrillar fAβ on the induction of microglial and astrocytic TN...
PMG and astrocytes were stimulated with fAβ, LPS, and TNF-α for 4, 12, and 20 hours. Afterwards, primary culture supernatants were analyzed for secreted TNF-α and CXCL10 levels using ELISA. (A) Schematic diagram. (B) A significant induction of TNF-α is detectable from 12 hours of fAβ stimulation in microglia culture (12 and 20 hours). (C) No TNF-α induction could be found in astrocytes after fAβ treatment over all analyzed time points. (D) fAβ and LPS induced similar levels of CXCL10 secretion at 12 and 20 hours. (E) Primary astrocytes do not respond to fAβ with increased CXCL10 secretion compared with unstimulated controls. Administration of TNF-α strongly stimulates astrocytes to produce CXCL10 after 4 hours. Data are shown as mean ± SEM from 2 to 3 individual experiments. *P < 0.05; **P < 0.01; ***P < 0.001 (1-way ANOVA, Dunn’s post hoc test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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