Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: A potential mechanism leading to chronic inflammation

https://doi.org/10.1016/j.expneurol.2008.09.003Get rights and content

Abstract

Inflammatory activation of microglia in response to neurodegenerative changes in diseases such as Alzheimer's disease (AD) and Parkinson's disease has been extensively described. These observations have suggested that inflammation could be contributing to disease progression. In this paper, the potential role of CD200 and CD200 receptor (CD200R), whose known functions are to activate anti-inflammatory pathways and induce immune tolerance through binding of CD200 to CD200 receptor (CD200R), was studied in AD. Quantitative studies showed a significant decrease in CD200 protein and mRNA in AD hippocampus and inferior temporal gyrus, but not cerebellum. Immunohistochemistry of brain tissue sections of hippocampus, superior frontal gyrus, inferior temporal gyrus and cerebellum from AD and non-demented cases demonstrated a predominant, though heterogeneous, neuronal localization for CD200. Decreased neuronal expression was apparent in brain regions affected by AD pathology. There was also a significant decrease in CD200R mRNA expression in AD hippocampus and inferior temporal gyrus, but not cerebellum. Low expression of CD200R by microglia was confirmed at the mRNA and protein level using cultured human microglia compared to blood-derived macrophages. Treatment of microglia and macrophages with interleukin-4 and interleukin-13 significantly increased expression of CD200R. Expression of these cytokines was not generally detectable in brain. These data indicate that the anti-inflammatory CD200/CD200R system may be deficient in AD brains. Mechanisms aimed at increasing levels of CD200 and CD200R could have therapeutic potential for controlling inflammation in human neurodegenerative diseases.

Introduction

The role of inflammation in contributing to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) has been intensively studied since the identification of prominent responses by microglia (brain resident macrophages) to degenerative structures in brain tissues affected by these diseases (Neuroinflammation Working Group, 2000, Hirsch et al., 2003). Pathological studies of AD indicated that the presence of activated microglia, reactive astrocytes, and complement activation, particularly in association with amyloid beta (Aβ)-containing plaques, demonstrated that a type of chronic inflammation was ongoing (McGeer and McGeer, 2003, Xiang et al., 2006, Sastre et al., 2006). A range of in vitro studies using cultured microglia from humans or rodents demonstrated that aggregated Aβ peptide could activate microglia to a proinflammatory state (Walker et al., 2006, Chen et al., 2005, Combs et al., 2001, Giulian et al., 1998, Gan et al., 2004, Yan et al., 1996). As activated microglia have the potential to produce a wide range of neurotoxic molecules, it was hoped that anti-inflammatory therapies might provide new targets for treating this disease (Launer, 2003, MacKenzie and Munoz, 1998, McGeer et al., 1996). Similarly, pronounced microglial responses were observed in the substantia nigra of PD patients, again establishing a neuroinflammatory component to this disease (Hirsch et al., 2003, McGeer et al., 1988bMcGeer et al., 1988a, Teismann et al., 2003). Since clinical trials with anti-inflammatory agents did not generally show effectiveness at slowing the progression of AD, other inflammatory therapeutic targets need to be considered. These targets can include enhancing the function of endogenous immune regulatory molecules. One such immunoregulatory system involves CD200 and CD200 receptor (CD200R). CD200 is a type-1 membrane glycoprotein of the immunoglobulin superfamily (IgSF) of cell surface proteins. It contains 2 IgSF domains and is expressed in a variety of lymphoid and non-lymphoid cells, including kidney glomeruli, vascular endothelium, and subsets of neurons. It was shown that CD200 was expressed by various populations of neurons in rodent brains (Barclay et al., 2002, Wright et al., 2001), but its neuroanatomy and biochemistry in human brain, and involvement in human neurodegenerative diseases such as AD, has not been studied extensively. CD200 (previously known as OX2) was studied for a number of years before being identified as the ligand for a myeloid cell receptor that became designated CD200 receptor (CD200R) (Wright et al., 2003, Wright et al., 2000). CD200R is a closely related molecule to CD200, also having two IgSF domains (Vieites et al., 2003), and is primarily expressed by myeloid cells (e.g. macrophages, neutrophils, monocytes and microglia) (Gorczynski et al., 2004, Voehringer et al., 2004, Vieites et al., 2003, Hatherley and Barclay, 2004). CD200R is a highly glycosylated protein with a molecular weight ranging from 60 to 110 kDa depending on the degree of glycosylation and expressing cell type; four separate CD200R-related genes have been identified in humans (Wright et al., 2003).

There is a growing body of data on the significance of CD200/CD200R in modulating tissue inflammation in various inflammatory diseases (Barclay et al., 2002, Elward and Gasque, 2003, Gorczynski et al., 2002a, Gorczynski et al., 2002b). Their interaction is also involved in inducing immune tolerance, and the prevention of tissue rejection (Clark et al., 2003, Rosenblum et al., 2004). In addition, increased expression of CD200 has been demonstrated in a number of cancers (Kretz-Rommel et al., 2007, Moreaux et al., 2008, Siva et al., 2008). For example, increased expression of CD200 in melanoma cells correlated with their metastatic potential, similarly CD200 expression by multiple myelomas correlated with the survival outcome of patients (Petermann et al., 2007, Siva et al., 2008, Moreaux et al., 2006). Increased CD200 expression appears to enhance the ability of cancer cells to escape immunological removal. CD200 has many features of related cell adhesion molecules; however, there is no evidence that it can activate intracellular signaling pathways. It has been shown that an interaction between the extracellular domains of CD200 and CD200R is necessary for the activation of anti-inflammatory signals by CD200R (Chen and Gorczynski, 2005, Hatherley and Barclay, 2004). Activation of the ERK, JNK, and p38 mitogen activated protein kinase (MAPK) pathways was inhibited by CD200R engagement with CD200 (Zhang et al., 2004). It has been demonstrated that responsiveness to CD200 was dependent on the level of expression of CD200R (Jenmalm et al., 2006). Monocytic cell lines that expressed high, medium, low or very low amounts of CD200R were treated with CD200 and then challenged with interferon-γ (IFN-γ). The low and very low CD200R-expressing cells showed minimal inhibitory response to CD200, measured as reduction in secretion of interleukin (IL)-8, unless CD200R was further crosslinked by antibody, while cells expressing medium to high levels of CD200R showed significant inhibitory response to applied CD200 (Jenmalm et al., 2006).

The significance of CD200/CD200R interactions has been demonstrated from a number of animal studies. One study showed a decrease in CD200 mRNA expression in the hippocampus of rats with increasing age (Frank et al., 2006). Another study showed that mice lacking the CD200 gene had significantly greater numbers of activated monocytes/macrophages under constitutive conditions, and macrophage/microglial activation and inflammatory damage were exacerbated in these animals following injurious treatments (e.g. collagen-induced arthritis, facial nerve transaction, induction of experimental allergic encephalomyelitis (EAE)) (Hoek et al., 2000). Similarly, mice lacking CD200R1 expression showed enhanced tumor necrosis factor-α production in response to lipopolysaccharide, and a lack of ability by CD200 to suppress this inflammatory response (Boudakov et al., 2007). It was recently shown that the reduced susceptibility to EAE by the wld mutant mouse strain was due to enhanced neuronal expression of CD200, which aided in suppression of CNS inflammation (Chitnis et al., 2007). Blocking CD200 in wld mice with antibodies restored EAE pathology to control levels. In mice treated to develop experimental autoimmune uveoretinitis, both CD200 knockout mice and wild type mice treated with antibody to block CD200–CD200R interactions had enhanced inflammation and tissue damage compared to controls. By comparison, in the same model, wild type mice treated with CD200R agonist antibodies showed less tissue damage and inflammation (Banerjee and Dick, 2004, Copland et al., 2007). Interestingly, CD200 knockout mice that had been infected with toxoplasma in a murine model of Toxoplasma encephalitis were able to clear the parasite more effectively due to the stronger inflammatory response that occurred (Deckert et al., 2006). A recent study employing mRNA expression analysis of laser-dissected active and inactive multiple sclerosis lesions demonstrated downregulated expression of CD200 in both types of lesions, while CD200R expression was unaffected (Koning et al., 2007).

In this report, we compared the expression of CD200 and CD200R in brain tissues affected by AD and demonstrated a deficit of both. The expression patterns of CD200 were examined in human AD and ND brains in relation to AD pathology. We also demonstrated that CD200R expression by human microglia is significantly lower than by human macrophages, but that its expression in both cell types can be increased by the anti-inflammatory cytokines IL-4 and IL-13. Expression of both anti-inflammatory cytokines is generally lacking in human elderly brains.

Section snippets

Human brain tissues

Human brain tissue samples from non-demented (ND) and AD cases that had been diagnosed by a neuropathologist were obtained from the Sun Health Research Institute Brain Bank. Brain tissues were donated to the Sun Health Research Institute Brain and Body donation program with informed consent and the approval of the Sun Health Corporation Institutional Review Board (IRB). A total of 59 cases were used in this study; 28 of these cases were diagnosed as ND (10 female: 18 male with mean age 86.0 y).

Immunolocalization of CD200 in human elderly brain

The aim of this study was to characterize CD200 and CD200 receptor expression in elderly human brains, and to demonstrate whether there was a deficit in AD of one or both. Studies on CD200 expression in human brain have not previously been reported except to demonstrate neuronal expression in cerebellum, a brain region not affected by AD (Wright et al., 2001). Most of our studies at the protein level on human brain tissues (immunohistochemistry and immunoblot) were carried out using a custom

Discussion

In this report, we have focused on CD200 and CD200R expression in elderly human AD and ND brains, and also studied expression of CD200R in vitro in human neural-derived and macrophage cells. There have been many publications on potential roles for microglia and inflammation in AD pathogenesis (recent reviews Craft et al., 2005, Pereira et al., 2005), but studies of cellular anti-inflammatory systems in the brain are more limited. These systems include CD200/CD200R, CD47/CD172a and CD22/CD45 (

Acknowledgments

This work was supported by grants from the Alzheimer's Association and Michael J Fox Foundation for Parkinson's Research (DGW). The authors are indebted to Dr. Thomas G. Beach and Ms. Lucia Sue for providing tissue for these studies from the Sun Health Research Institute Tissue Bank. The Brain Donation Program is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s

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