CD200 dysfunction in neuron contributes to synaptic deficits and cognitive impairment

https://doi.org/10.1016/j.bbrc.2019.06.134Get rights and content

Highlights

  • Neuronal CD200 upregulation significantly improve cognitive function.

  • Specific elevated CD200 in neuron not alter amyloid plaque formation.

  • Neuronal CD200 upregulation prevent microglial activation induced synaptic dysfunction.

Abstract

Neuronal CD200 plays critical role in neuron-microglia communication and negatively related to pathological development of Alzheimer's disease, but its contribution retroacts to synaptic function is still not clear. Here, we directly injected adeno-associated virus into hippocampus of APP/PS1 mice to induce neuron-specific CD200 overexpression; subsequently, we detected cognition function, synaptic function, and the microglial responses during AD pathological development. Notably, specific upregulation of neuronal CD200 promoted cognitive function by inhibiting microglial activation and secretion, improving synaptic function, and preventing synaptic loss. To further investigate the role of neuronal CD200 on synaptic function, we depressed CD200 expression in neuron by hippocampal AAV injection and also evaluated microglial activation and cognitive and synaptic function. Interestingly, data revealed that neuronal CD200 deficiency significantly impairs synaptic and cognitive function. Taken these results together, we concluded that neuronal CD200 mediated microglial response and synaptic function during AD pathological development, and provided evidence that neuronal CD200 restoration ameliorates synaptic and cognitive deficits.

Introduction

Alzheimer's disease (AD) is characterized by progressive deficits in memory and cognitive function [1]. In AD pathology, the deposition of amyloid-beta (Aβ) and neurofibrillary tangles are thought to be related to the loss of neuronal populations and deficits in synaptic plasticity, which in turn contribute to functional decline [2]. The extracellular application of Aβ-related oligomers activates the microglial immune response [3] and immediately impairs synaptic plasticity and memory [4]. Furthermore, the degree of synaptic loss in AD is strongly related to cognitive decline [5].

Microglia are the brain's primary resident immune cells that work to maintain a homeostatic state through the activation of neuronal immunomodulators [6], such as CX3CL1 and CD200, and the regulation of developmental and adult hippocampal neurogenesis [7]. In addition, microglia are involved in the remodeling of neuronal circuits and synapses, including synaptogenesis, synaptic pruning, and synaptic plasticity, to improve cognitive functions [8,9]. In animal models of AD-like pathologies, microglia are attracted to amyloid plaques and promote Aβ clearance via internalization and degradation but also continuously produce pro-inflammatory mediators and mediate synaptic loss in AD when inappropriately hyperactivated [[10], [11], [12], [13]].

CD200 is present in neurons, astrocytes, and the vascular endothelium [14,15] where it acts as a so-called “don't eat me” signal that alters cell degradation via microglia and modulates the innate immune response [16]. The interaction between CD200 and the CD200 receptor (CD200R) aids in the maintenance of a relative resting state in microglia and suppresses microglial phagocytosis [17]. The CD200 extracellular motif contacts CD200R to phosphorylate the NPxY motif on cytoplasmic CD200R, accumulate tyrosine kinase 1 and 2 (Dok1 and Dok2), bind and activate RasGAP, and inhibit the activations of Ras, Erk, and PI3K [[18], [19], [20], [21]]. CD200 levels are lower in the hippocampus and inferior temporal gyrus of AD brains compared to age-matched controls, which suggests that these changes are associated with the initiation of neuronal loss and may influence age-related increases in microglial activation [22]. Similar decreases in CD200 levels have been identified in animal models of multiple sclerosis and Parkinson's disease [23,24]. On the other hand, CD200 fusion protein (CD200Fc) attenuates microglial activation and alters deficits in long-term potentiation (LTP) [25]. Furthermore, in an animal model of AD, hippocampal injections of AAV2/1-CD200 restore adult neurogenesis, reduce amyloid load, enhance Aβ phagocytosis by microglia, and increase the differentiation of neural stem cells [26].

Thus, the present study investigated whether cognitive functions would be influenced by the enhancement of neuronal CD200 in an animal model of AD that was established to achieve the upregulation of neuron-specific CD200. It turns out that the overexpression of neuron-specific CD200 improved cognitive function by preventing synaptic impairments without influencing amyloid plaque loading and microglial phagocytosis towards Aβ.

Section snippets

Animals

Male APP/PS1 [B6.Cg-Tg(APPswe, PSEN1ΔE9)85Dbo/Mmjax] and Thy1-EGFP [B6.Cg-Tg(Thy1-EGFP)OJrs/GfngJ] mice were purchased from model animal research center of Nanjing University (Nanjing, China) and used in this study. All animals were maintained with allowed standard mouse chow and water ad libitum under temperature- and humidity-controlled environment. And all experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the Shandong Province Experimental

Upregulation of neuron-specific CD200 improves cognitive function in APP/PS1 mice

To assess the impact of neuronal CD200 on cognitive function in an animal model of AD, AAV2/9-syn-CD200-mCherry was injected into the hippocampus of Thy1-EGFP-APP/PS1 mice at 2, 4, 6, 8, and 10 months to induce the overexpression of neuron-specific CD200 (Fig. S1A). Then hippocampal neurons were isolated (Fig. S1B) from the brains of CD200 OE-APP/PS1 mice using MACS and purity > 90% was identified using FACS (Figs. S1C and S1D) and the mRNA and protein levels of CD200 in primary hippocampal

Discussion

In this study, we established a model of Syn-CD200 OE-APP/PS1 mice that specifically overexpressed neuronal CD200 and interestingly demonstrated that the upregulation of neuron-specific CD200 alleviated spatial learning and memory deficits in an animal model of AD. However, the upregulation of neuronal CD200 did not alter the deposition of amyloid plaques, microglial responses to AD pathology, or the primary microglial phagocytosis FITC-Aβ42. On the other hand, the upregulation of neuronal

Conflict of interest

The authors have declared that no competing interest exists.

References (36)

  • D.A. Costello et al.

    Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation

    J. Biol. Chem.

    (2011)
  • E.G. Mcgeer et al.

    Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy

    J. Alzheimer's Dis.

    (2010)
  • M. et al.

    Extracellular Tau oligomers produce an immediate impairment of LTP and memory

    Sci. Rep.

    (2016)
  • S.T. Dekosky et al.

    Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity

    Ann. Neurol.

    (1990)
  • A. Nimmerjahn et al.

    Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

    Science

    (2005)
  • K. Reemst et al.

    The indispensable roles of microglia and astrocytes during brain development

    Front. Hum. Neurosci.

    (2016)
  • E.E. Spangenberg et al.

    Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology

    Brain

    (2016)
  • S. Prokop et al.

    Microglia actions in Alzheimer's disease

    Acta Neuropathol.

    (2013)
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