This project tests the central hypothesis that increased oligodendroglial oxidative stress promotes dysmyelination of the aging CNS through specific mediators of membrane lipid peroxidation (MLP) that are subject to environmental regulation. The studies will employ an in vitro approach to identify mechanisms of oxidative injury and glioprotection in the oligodendrocyte (OC)-myelin unit, modeled with myelinogenic OCs grown to maturity in isolation from other cell types. Experiments in Aim 1 will determine the identity of proteins of the myelin membrane and associated microtubule cyrtoskeleton adducted by 4- hydroxynonenal (HNE), a highly reactive cytotoxic effector of MLP- mediated injury implicated in neurodegenerative diseases of aging. They will further examine the peturbing effect of HNE on the amount and integrity of myelin-like membrane biogenesis, microtubule assembly and microtubule-dependent translocation of myelin basic protein mRNA to the myelin compartment in living cells. Experiments in Aim 2 will identify the capacity of specific environmental signals instrumental to differentiation and/or maintenance of the OC-myelin unit to regulate anti-oxidant defenses in myelinogenic OCs. They will identify specific diffusible factors and non-diffusible homotypic and heterotypic cell-cell interactions that suppress the generation of reactive oxygen species and cellular injury, using a menadione model for oxyradical production, and determine whether regulation occurs to stimulate glutathione biosynthesis and/or oxyradical-detoxifying enzyme activities. Experiments in Aim 3 will determine the capacity of estrogens and melatonin, both recognized as natural neuroprotectants with antioxidant activity, and non-pschycotropic cannabinoid to protect myelinogenic OCs against HNE and reactive oxygen species evoked by oxyradical generators and pro-oxidants of neuropathologic significance to aging (glutamate, beta-amyloid peptide. Successful completion of these aims will indicate biochemical loci where therapeutic intervention may suppress acute and chronic forms of oxidative stress in OCs and reduce morbidity consequent to dysmelination in normal and pathologic aging.
| Gard, A L; Gavin, E; Solodushko, V et al. (2004) Cardiotrophin-1 in choroid plexus and the cerebrospinal fluid circulatory system. Neuroscience 127:43-52 |
| Gard, A L; Solodushko, V G; Waeg, G et al. (2001) 4-Hydroxynonenal, a lipid peroxidation byproduct of spinal cord injury, is cytotoxic for oligodendrocyte progenitors and inhibits their responsiveness to PDGF. Microsc Res Tech 52:709-18 |
