Biochemical and Biophysical Research Communications
CD200 dysfunction in neuron contributes to synaptic deficits and cognitive impairment
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)
- et al.
Alzheimer's disease genetics: from the bench to the clinic
Neuron
(2014) - et al.
Deciphering the molecular basis of memory failure in Alzheimer's disease
Neuron
(2004) - et al.
Microglia in neuronal plasticity: influence of stress
Neuropharmacology
(2015) - et al.
Anti-inflammatory signaling in microglia exacerbates Alzheimer's disease-related pathology
Neuron
(2015) - et al.
CD200 and membrane protein interactions in the control of myeloid cells
Trends Immunol.
(2002) - et al.
Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: a potential mechanism leading to chronic inflammation
Exp. Neurol.
(2009) - et al.
CD200 fusion protein decreases microglial activation in the hippocampus of aged rats
Brain Behav. Immun.
(2012) - et al.
The anti-inflammatory glycoprotein, CD200, restores neurogenesis and enhances amyloid phagocytosis in a mouse model of Alzheimer's disease
Neurobiol. Aging
(2015) - et al.
Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function
Immunity
(2000) - et al.
Neuroinflammation in Alzheimer's disease
Lancet Neurol.
(2015)