P2‐177: Why is the aging brain predisposed to Alzheimer disease and how do we reverse it?

Background: Aging remains the leading epidemiological factor in Alzheimer’s disease, yet few studies try to understand what about aging contributes to the disease. Aging may be the final stage of development under epigenetic control or aging may result from lost mitochondrial function. Epigenetic changes are potentially reversible by histone deacetylase inhibitors. Mitochondrial ROS damage may be reversed by stimulated autophagy, mitochondrial biogenesis and enhanced glutathione synthesis. Here we demonstrate such reversibility in mitochondrial function and neuron survival by four agents: trichostatin A, estrogen, blueberry extract and rapamycin. Methods: Neurons were isolated from embryonic, 10 and 24 month Fisher rat hippocampus and cultured in a common medium environment to control for aging hormonal and vascular differences. Single neuron analyses were conducted with appropriate fluorescent probes. Results: Old neurons survive isolation and regenerate dendrites in culture as well as middle-age brain neurons. Resting respiration of old neurons is similar to middle-age as are the number of mitochondria/neuron. The following agerelated changes suggest cryptic intrinsic alterations are exposed under stress. Old neurons lose regulation of Ca dynamics which can be rejuvenated by estrogen. The mitochondrial membrane potential is partially depolarized with higher levels of ROS, loss of NADH and redox potential in old rat neurons. Respiration of old neurons fails to increase with glutamate due to agerelated deficits in complex IV, cytochrome C oxidoreductase (CCO) that were reversed by estrogen. The age-related death of neurons from exposure to beta-amyloid was greatly attenuated by exposure to blueberry extract through a transient rise in ROS with subsequent increases in the redox buffer glutathione. Another part of the age-related vulnerability may be defective autophagy to remove damaged mitochondria. We found that stimulation of autophagy with rapamycin improved survival of old neurons treated with A-beta. Lastly, we found that low doses of the histone deacetylase inhibitor trichostatin A stimulated acetylation of histone-3 coincident with rescue of old neurons from A-beta toxicity. Conclusions: New evidence points to abiding impairment by epigenetic control in old neurons that can be rejuvenated by estrogen, blueberry extract, epigenetic regulators or stimulation of autophagy.