The Role of CXCR3 in Neurological Diseases

Zhou, Ya-Qun; Liu, Dai-Qiang; Chen, Shu-Ping; Sun, Jia; Zhou, Xue-Rong; Xing, Cui; Ye, Da-Wei; Tian, Yu-Ke

Alzheimer's disease (AD) is one of the most prevalent progressive neurodegenerative brain disorders worldwide characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions [68, 69] . Chemokines and their receptors were found to be associated with AD pathological changes [70] [71] [72] [73] . Using post-mortem human tissues of AD patients, Xia et al. [72] provided the first immunohistochemical evidence that CXCR3 was constitutively expressed on a subpopulation of neurons and neuronal processes in the neocortex, hippocampal formation, striatum, cerebellum and spinal cord. Moreover, they found greatly upregulated CXCL10 positive astrocytes in AD patients compare with controls. Additionally, CXCL10 positive astrocytes were frequently associated with amyloid deposits, suggesting an active chronic inflammatory response related to amyloid deposits occurs in AD patients. Recently, Krauthausen et al. [22] examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. They found that amyloid beta (Aβ) deposition and Aβ levels were significantly decreased in CXCR3 _ / _ APP/PS1 mice compared with control APP/PS1 mice. Their in vitro and in vivo analysis of microglial phagocytosis showed that CXCR3 deficiency facilitated the microglial uptake of Aβ. Moreover, preincubation of CXCR3 antagonist increased primary microglial Aβ phagocytosis and reduced TNF-α secretion. Compared with control APP/PS1 mice, brain tissue from CXCR3 _ / _ APP/PS1 mice had reduced concentrations of proinflmmatory cytokines and the microglia exhibited obvious morphological activation and reduced plaque association. Furthermore, Morris watermaze testing showed improved spatial memory of CXCR3 _ / _ APP/PS1 mice compared with controls, suggesting that lack of CXCR3 attenuated the behavioral deficits of APP/PS1 mice. Taken together, these results indicated that CXCR3 signaling mediated development of AD-like pathology in APP/PS1 mice and suggested that CXCR3 had the potential to be a therapeutic target for AD. Furthermore, a very recent study reported that peripheral blood mononuclear cells of Alzheimer's disease patients control CCL4 and CXCL10 levels in a human blood brain barrier model. These studies indicated a pivotal role of CXCR3 in the pathogenesis of AD. However, further studies are warranted to explore the underlying mechanisms.