Expression of the receptor for advanced glycation end products in oligodendrocytes in response to oxidative stress

Abstract

Demyelination is a common result of oxidative stress in the nervous system, and we report here that the response of oligodendrocytes to oxidative stress involves the receptor for advanced glycation end products (RAGE). RAGE has not previously been reported in neonatal rat oligodendrocytes (NRO), but, by using primers specific for rat RAGE, we were able to show expression of messenger RNA (mRNA) for RAGE in NRO, and a 55-kDa protein was detected by Western blotting with antibodies to RAGE. Neonatal rat oligodendrocytes stained strongly for RAGE, suggesting membrane localization of RAGE. Addition of low concentrations of hydrogen peroxide (100 μM) initiated 55-kDa RAGE shedding from the cell membrane and the appearance of "soluble" 45-kDa RAGE in the culture medium, followed by restoration of RAGE expression to normal levels. Increasing hydrogen peroxide concentration (>200 μM) resulted in no restoration of RAGE, and the cells underwent apoptosis and necrosis. We further confirmed the observation in a human oligodendroglioma-derived (HOG) cell line. Both the antioxidant N-acetyl-L-cysteine and the broad-spectrum metalloproteases inhibitor TAPI0 were able partially to inhibit shedding of RAGE, suggesting involvement of metalloproteases in cleavage to produce soluble RAGE. The level of 55-kDa RAGE in autopsy brain of patients undergoing neurodegeneration with accompanying inflammation [multiple sclerosis and neuronal ceroid-lipofuscinosis (Batten's disease)] was much lower than that in age-matched controls, suggesting that shedding of RAGE might occur as reactive oxygen species accumulate in brain cells and be part of the process of neurodegeneration. Keywordsoligodendrocytes; reactive oxygen species; hydrogen peroxide; RAGE; shedding proteolysis Oligodendrocytes have been implicated in the pathogenesis of demyelinating diseases such as multiple sclerosis (MS) in which the active agents are reactive oxygen species (ROS) and the products of inflammation (LeVine, 1992;Smith et al., 1999). Evidence of ROS damage has been reported in demyelinating lesions in the brains of MS patients (Langemann et al., 1992;LeVine and Wetzel, 1998) and in the demyelinating experimental allergic encephalitis (EAE) mouse spinal cord (MacMicking et al., 1992). Lipid peroxidation products and ROS have been identified in cerebrospinal fluid (CSF), plasma, and brain from MS patients (Naidoo and Knapp, 1992;LeVine, 1992;Qin et al., 2007), and this, together with evidence for peroxynitrite modification of proteins (Liu et al., 2001) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1998), strongly supports the view that oxidative damage is important in demyelination. Protein carbonyl content, mainly glutamic semialdehyde (from arginine and proline) and aminoadipic semialde-hyde (from lysine oxidation), is a measure of ROS-mediated protein oxidation (Berlett and Stadtman, 1997) and is increased in MS brain (Bizzozero et al., 2005).RAGE is a 45−55-kDa member of the immunoglobulin superfamily (Rong et al., 2004a,b;...

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