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

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.

Systemic Inflammation Modulates Fc Receptor Expression on Microglia during Chronic Neurodegeneration

“…For example, proinflammatory cytokines can significantly increase the expression of receptors that signal through ITAM motifs, lowering the threshold for activation (33). Microglia express several members of this family, including FcgR, TREM-2, SIRPb1, DAP12, and CD200R (34)(35)(36), and there is evidence that the loss of inhibitory signals results in microglial priming, making them more prone to activation (37). The current study shows increased expression of both ITAM-and ITIM-bearing receptors in ME7 animals at the mRNA level and on microglia at the protein level.…”

The Evolving Biology of Microglia in Alzheimer's Disease

“…These findings suggest that, as in EAE, CD200/200R signaling might be neuroprotective in AD. However, CD200 expression is downregulated in rats following intraventricular injection of Aβ [106], and both CD200 and CD200R levels are reduced in patients with AD, particularly in parts of the brain that exhibit the highest plaque burden [107]. Thus, downregulation of CD200/200R signaling may provide a permissive environment for development of AD pathology.…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…On the other hand, it has been noted that neurons are able to generate various molecules that are demonstrated to suppress inflammation, such as TREM2, CD22, CD200, CD59 and fractalkine (Hsieh et al 2009;Mott et al 2004;Ransohoff 2007;Singhrao et al 1999;Walker et al 2009). Interestingly, several of these molecules have been found to be deficient in AD.…”

“…Interestingly, several of these molecules have been found to be deficient in AD. For instance, the expression of CD200 and CD59 was reported to be down-regulated in neurons of AD brain (Walker et al 2009;Yang et al 2000). Generally, studies in the expression of inflammatory molecules in neurons of AD individuals are still not fully explored, and more investigations into this area are needed.…”