Differential Responses to Oxidative Stress in the Brain of Normal Aged Humans Versus Alzheimer's Disease





A.C. Andorn, P.C. Bickford, D. Hogan

Department of Psychiatry and Behavioral Science University of Texas Medical Branch 301 University Blvd. Galveston, TX 77555-0431



Organisms are repetitively exposed to oxygen radicals during their lifespan. When the oxygen radical trapping mechanisms of the cell or organism are insufficient for the oxygen radical load, a state of oxidative stress exists. There is evidence that exposure of cells or organisms to exogenously applied sublethal oxidative stress promotes adaptive mechanisms that may be unrelated to the cell’s or organism’s ability to trap oxygen radicals. This adaptive response raises the lethal threshold for not only the original oxidative stressor but for oxidative stressors of different classes. Recent reports have demonstrated an increase in the concentration of reactive oxygen species (ROS) in aged rat brain but a decreased responsiveness of CNS tissue to exogenously applied near lethal doses of an oxidant stressor confirming that this mechanism of adaptation may apply to aging CNS. In spite of this, signs of the consequences of oxidative stress are well documented in aged CNS. In neurodegenerative diseases, the magnitude of oxidative stress in the areas of pathology is invariably much greater than in age-matched control CNS. We have hypothesized that some adaptation to oxidative stress occurs in normal aged CNS. We have further hypothesized that there is a failure of this adaptive process in vulnerable areas of the CNS in Alzheimer’s disease (AD). We have found that when physiologic concentrations of an oxidative stressor (0.1 mM ascorbate) are used, extensively washed membrane fragment preparations from AD prefrontal cortex are hypo-responsive compared to age-matched control, which trend toward the hypo-responsive as compared to young. When we examined the response of membrane fragment preparation from human prefrontal cortex to ascorbate in greater detail, we observed the following. Ascorbate stimulated lipid peroxidation in young proceeded rapidly and was a complex multistep process best modeled by a fourth order polynomial. In contrast. ascorbate stimulated lipid peroxidation in membrane fragments from aged proceeded by a rapid but less complex process best modeled by a third order polynomial. Importantly, in AD, the rapid production of lipid peroxidation in the presence of ascorbate occurred by apparently the same complex process as in young, but the magnitude of the response was reduced. Next we studied young (3 month) and aged (24 month) rats exposed to either control diet or to the antioxidant PBN for two weeks prior to sacrifice. We performed the same ascorbate kinetic studies in the cortices from these rat brains as we did on the human cortices. Aged rats treated with antioxidants had kinetic parameters most closely approximating young control rats. Unexpectedly, young rats treated with PBN had kinetic indices more closely resembling aged rats. Taken together these findings suggest that indeed aged CNS has different responsiveness not only to oxidant stress but also to antioxidants as compared to young. The fact that AD brain most closely resembles young with regard to the kinetics of ascorbate stimulated lipid peroxidation suggests that the response of AD brain to antioxidants might not be similar to the response of aged brain.




Key words: Oxidative stress, human brain, Alzheimer's disease







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