Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents.
Neurons and glia within the hippocampus of aged, spatial learning-impaired Long-Evans rats exhibit uniquely altered gene expression profiles, and we have postulated oxidative stress as the basis for this. To test this hypothesis we quantitated the extent of protein and nucleic acid oxidative damage, evaluated the status of mitochondrial DNA integrity, and examined several signaling entities and molecular indicators frequently associated with oxidative stress and gliosis. Immunoblotting demonstrated elevated heme oxygenase-1 in the aged-impaired hippocampus and immunocytochemistry suggested that heme oxygenase-1 is largely cytosolic and at least partly neuronal in nature. In the aged-impaired group, immunoreactivity to 8-hydroxy-2'-deoxyguanosine, an oxidative nucleic acid adduct, was found to be elevated in the dentate gyrus and in area CA1 of the hippocampal formation. Isolated mitochondrial DNA was found to be significantly damaged in the aged-impaired group. In the aged learning-impaired rats only, proteins in a 65-kDa band were found to contain excessive levels of carbonyl residues. Glial activation was examined by in situ hybridization histochemistry to tumor necrosis factor alpha and by immunocytochemistry with OX-6, which detects activated microglia. White matter in aged brains exhibited a modest up-regulation of tumor necrosis factor alpha mRNA and OX-6 immunoreactivity, but the hippocampal formation expressed tumor necrosis factor alpha mRNA equivalent to young animals and few OX-6-positive microglia. The mRNA for manganese-dependent superoxide dismutase, which is elevated in the aged hippocampus, was found preferentially expressed in neurons. We conclude that aged hippocampal neurons appear to be under oxidative stress and this is more severe in the learning-impaired subjects, suggesting a possible basis for age-induced cognitive decline.
Nicolle
M M
MM
Mayo Clinic, Department of Pharmacology, Jacksonville, FL 32224, USA.
Gonzalez
J
J
Sugaya
K
K
Baskerville
K A
KA
Bryan
D
D
Lund
K
K
Gallagher
M
M
McKinney
M
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D004272:DNA, Mitochondrial / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006624:Hippocampus / Q000378:metabolism*; D007859:Learning Disabilities / Q000378:metabolism* / Q000523:psychology; D008297:Male; D009474:Neurons / Q000378:metabolism; D009696:Nucleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013028:Space Perception / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004272:DNA, Mitochondrial; D009696:Nucleic Acids; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase