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

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

doi:10.1172/jci66771

Cited by 115 publications

(92 citation statements)

References 97 publications

(113 reference statements)

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“…Our study suggests that blocking CXCR3 is beneficial and warrants further investigation of this pathway in TON as well as evaluation of the effects of a number of CXCR3 antagonists, which are in clinical development for treating inflammatory diseases in human subjects. This study, together with previous findings that deleting CXCR3 prevents retinal neuronal cell death after an acute increase in intraocular pressure, 21 prolongs survival times after prion infection, 57 reduces NMDA-induced neuronal cell death in brain, 58 and attenuates plaque formation and behavioral deficits in Alzheimer disease, 59 highlights a role of CXCR3 in neurodegenerative diseases. The CXCL10/CXCR3 axis plays a critical role in inflammation by recruiting activated T lymphocytes, monocytes, and macrophages.…”

Section: Discussionsupporting

confidence: 81%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. (Am J Pathol 2017, 187: 352e365; http://dx

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Section: Discussionsupporting

confidence: 81%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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“…Dysregulated neuronmicroglia communication has been implicated in neurodegenerative diseases (92). Studies using murine models of AD have demonstrated that chemokine receptors influence AD pathology by modulating several aspects of microglial function, such as accumulation, clustering, and phagocytosis (93)(94)(95)(96). Loss of the chemokine receptor CXCR3 in APP/PS1 mice reduced Aβ burden and inflammation while increasing BDNF expression and improving behavioral deficits (95).…”

Section: Loss Of Inhibitory Signalsmentioning

confidence: 99%

“…Studies using murine models of AD have demonstrated that chemokine receptors influence AD pathology by modulating several aspects of microglial function, such as accumulation, clustering, and phagocytosis (93)(94)(95)(96). Loss of the chemokine receptor CXCR3 in APP/PS1 mice reduced Aβ burden and inflammation while increasing BDNF expression and improving behavioral deficits (95). Thus, CXCR3 signaling is involved in the suppression of microglial Aβ phagocytosis in APP/PS1 mice, ultimately leading to an increase of Aβ plaque deposition.…”

Section: Loss Of Inhibitory Signalsmentioning

confidence: 99%

Microglia in Alzheimer’s disease

Sarlus

Heneka

2017

Journal of Clinical Investigation

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673

561

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“…These mutations are believed to have a close relationship with the excessive formation of Aβ plaques. Extracellular Aβ deposition can be detected in such Tg mouse models at 2.5 months [18,19], longterm potentiation impairment at 3 months [20], apparent dysfunction of learning and memory at 6 ~ 8 months [21,22], and a small amount of Aβ deposition in hippocampus at 6 months [23], SP in hippocampus at 8 months and cerebral cortex similar with AD patients and neuron loss at 12 ~ 18 months [24]. However, some studies found that along with the growth of mice, cerebral glucose uptake increased, especially around the SP, and the mechanism of which need to be further explored [25].…”

Section: App/ps1 Tg Mouse Modelmentioning

confidence: 99%

Application of APP/PS1 Transgenic Mouse Model for AlzheimerÃ¢ÂÂs Disease

Li¹,

Wei²,

Wang³

et al. 2015

J Alzheimers Dis Parkinsonism

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Alzheimer's disease (AD), the most common neurodegenerative disorder, will not only reduce quality of life severely, but also bring heavy economic burden to the family and society. Slow progress in AD therapies partially due to lack of appropriate animal models. APP/PS1 transgenic mouse, a widely used animal model for AD, can be used in lots of aspects for AD related study, such as neuronal apoptosis, inflammation, cholinergic abnormal, neurogenesis disorder and synaptic plasticity. Despite all this, APP/PS1 transgenic mice model is not a perfect model, and more suitable animal model according to the aim of research should be established. mutant, the APP KI mutation alone does not affect markers for adult hippocampal neurogenesis [12]. PS1 KI mice, a model that shows cognitive decline developed in an Aβ-independent way, therefore plaque-dependent pathology cannot be expected [13].Tg models are important models for the AD study. They are established on the basis of genetics, mainly involves amyloid precursor protein(APP) gene on chromosome 21, presenilin1 (PS1) gene on chromosome 14, presenilin 2 (PS2) gene on chromosome 1, Tau protein gene on chromosome 17 and Apolipoprotein E (ApoE) gene on chromosome 19 [14]. By transgenesis, the course of AD can be simulated steadily at molecular level. Meanwhile, this technique can produce many animals at the same time, so the reliability and repeatability of experimental results can be ensured. Tg models have three types: single transgenic models such as APP Tg mouse model, double Tg models such as APP/PS1 Tg mouse model and triple Tg mouse models such as APP/ PS1/Tau Tg mouse model [15]. Although the emergence of Tg model is a hot spot of AD research in recent years, there are still problems in the application of Tg AD models, such as lack of aging process, poor reproductive ability and immunity. Therefore, compared with the real AD pathological changes, there is still a long way to go. APP/PS1 Tg mouse model

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

Cited by 115 publications

References 97 publications

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Microglia in Alzheimer’s disease

Application of APP/PS1 Transgenic Mouse Model for AlzheimerÃ¢ÂÂs Disease

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

Cited by 115 publications

References 97 publications

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Microglia in Alzheimer’s disease

Application of APP/PS1 Transgenic Mouse Model for AlzheimerÃ¢ÂÂs Disease

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Product

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Application of APP/PS1 Transgenic Mouse Model for AlzheimerÃ¢ÂÂs Disease