Aging- and oxygen-induced modifications in brain biochemistry and behavior.
In summary, the work presented here has shown accumulation of oxidized protein with age in an animal aging model. In gerbil brain, this accumulation is associated with (1) decreased activity of oxidatively sensitive enzymes creatine kinase and glutamine synthetase; (2) decreased function of particular cytoskeletal proteins; and (3) decreased performance in a radial-arm maze task. Manipulations shown to increase the presence of reactive oxygen species in the brain increase oxidized protein, decrease the index enzyme activities and cytoskeletal protein defects, and worsen performance deficits. Moreover, intervention designed to quench ROS-mediated reactions decrease oxidized protein levels, and nearly normalize index enzyme activities and associated behavioral deficits. The precise connections between the performance deficits and protein measures are probably highly complex and likely to remain obscure for now. Currently, the behavioral measures serve as a marker for the functional consequences of the protein alterations. Our studies in humans have shown oxidized protein accumulation with age and a differential decrease of glutamine synthetase activity in the frontal lobe in AD. Further preliminary results in AD autopsy material show a striking correlation between the distribution of index enzyme inactivation and the known intensity distribution of AD pathology. These findings support the hypothesis that inability to restrain age- or pathology-related increases in local ROS activity can result in AD.
Department of Pharmacology, University of Kentucky, Lexington 40506.
J M
JM
Carney
C D
CD
Smith
A M
AM
Carney
D A
DA
Butterfield
D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001344:Autopsy; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism*; D003402:Creatine Kinase / Q000378:metabolism; D005849:Gerbillinae; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning; D008568:Memory; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009928:Organ Specificity; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D015427:Reperfusion Injury / Q000378:metabolism; D013028:Space Perception
D000596:Amino Acids; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D003402:Creatine Kinase; D005974:Glutamate-Ammonia Ligase