Expression of the receptor for advanced glycation end products in oligodendrocytes in response to oxidative stress.
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 microM) 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 microM) 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.
Qin
Jingdong
J
Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA.
Goswami
Rajendra
R
Dawson
Sylvia
S
Dawson
Glyn
G
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D004791:Enzyme Inhibitors; D016877:Oxidants; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D006861:Hydrogen Peroxide