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Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer’s Disease

Molecular Neurobiology volume 54, pages 7964–7978 (2017)Cite this article

Abstract

The majority of Alzheimer’s disease (AD) patients have a late onset, and chronic neuroinflammation, characterized by glial activation and secretion of pro-inflammatory cytokines and chemokines, plays a role in the pathogenesis of AD. The chemokine CCL11 has been shown to be a causative factor of cognitive decline in the process of aging, but little is known whether it is involved in the pathogenesis of AD. In the present study, we showed that CCR3, the receptor for CCL11, was expressed by hippocampal neurons and treatment of primary hippocampal neuronal cultures (14 days in vitro) with CCL11 resulted in activation of cyclin-dependent kinase 5 and glycogen synthase kinase-3β, associated with elevated tau phosphorylation at multiple sites. CCL11 treatment also induced the production of Aβ and dendritic spine loss in the hippocampal neuronal cultures. All these effects were blocked by the CCR3 specific antagonist, GW766994. An age-dependent increase in CCL11, predominantly expressed by the activated microglia, was observed in the cerebrospinal fluid of both APP/PS1 double transgenic mice and wild-type (WT) littermates, with a markedly higher level in APP/PS1 double transgenic mice than that in WT littermates. Deletion of CCR3 in APP/PS1 double transgenic mice significantly reduced the phosphorylation of CDK5 and GSK3β, tau hyperphosphorylation, Aβ deposition, microgliosis, astrogliosis, synaptic loss, and spatial learning and memory deficits. Thus, the age-related increase in CCL11 may be a risk factor of AD, and antagonizing CCR3 may bring therapeutic benefits to AD.

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Acknowledgements

We thank Dr. Guo-Huang Fan, professor in Tongji University for the helpful discussion. This work was supported by the National Natural Science Foundation of China (ID81371395), Liaoning Provincial Natural Science Foundation (ID 2015020547), and China Post-doctoral Science Foundation (ID 2015 M581375) to Yi Sui.

Author’s Contribution

YS designed the experiments, oversaw the whole project, and prepared the manuscript. CZ performed the experiments in Figs. 1, 2, and 5 and prepared the manuscript. BX performed the experiments in Figs. 3 and 4. XS performed the experiments in Fig. 6. QZ performed the experiments in Fig. 6

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Affiliations

  1. Department of Neurology, Shenyang Seventh People’s Hospital, Shenyang, China

    Chunyan Zhu

  2. Department of Neurology, Shenyang First People’s Hospital, Shenyang Brain Hospital, Shenyang Brain Institute, Shenyang, China

    Bing Xu & Yi Sui

  3. Department of Neurology, the Fourth Affiliated Hospital, China Medical University, Shenyang, China

    Xiaohong Sun & Yi Sui

  4. Key laboratory of Behavioral and Cognitive Neuroscience of Liaoning Province, Shenyang Medical College, Shenyang, China

    Qiwen Zhu & Yi Sui

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  1. Chunyan Zhu
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  2. Bing Xu
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  3. Xiaohong Sun
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  4. Qiwen Zhu
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  5. Yi Sui
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Correspondence to Yi Sui.

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Zhu, C., Xu, B., Sun, X. et al. Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer’s Disease. Mol Neurobiol 54, 7964–7978 (2017). https://doi.org/10.1007/s12035-016-0269-5

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  • DOI: https://doi.org/10.1007/s12035-016-0269-5

Keywords

  • CCR3
  • Alzheimer’s disease
  • CCL11
  • β-amyloid
  • Tau
  • Hyperphosphorylation
  • Synapse