Age-related Response of Hippocampal Neurons to Stress P.I.: Brewer, Gregory J. ABSTRACT Age remains the most significant unexplained etiologic factor in common neurodegenerative diseases. The issue of age is brought into sharper focus by the question, what is it about aging that causes people with congenital mutations in APP or presenilin to wait decades before invariably developing Alzheimer disease (AD) with cognitive deficits and brain pathology? Our previous NIA grant began to investigate the aging component for neurons from aging (24 mo.) compared to middle-age rats (9 mo.). The results firmly established the higher intrinsic susceptibility of old rat neurons to stressors such as glutamate and A?, particularly in mitochondrial function and bioenergetics. These changes must be intrinsic to old neurons because they remain in common culture conditions after removal from the aging hormone, immune and vasculature system environments. Our data suggest explicitly enhanced resting mitochondrial production of reactive oxygen species (ROS), low glutathione (GSH) and NADH and depolarized mitochondrial membrane potential (MMP). Other parameters such as viability in the common culture medium, mitochondrial number per cell and resting respiration are not different. Most importantly, most of the impairments are only evident after treatment with glutamate or A?. While evidence for age-related damage to nucleic acids, proteins and lipids abound, the proposed studies will strategically focus on the sources or conditions that promote this damage. Specifically, it is proposed that aging increases susceptibility to stressors like glutamate and A? by an incremental failure of the essential signaling functions of ROS redox control. Since energy supply is so critical to synaptic function, Aim 1 will determine the cause of the age-related depolarization of the MMP and higher levels of ROS in old rat neurons and also examine inefficient autophagy in old neurons due to lower turnover of mitochondria.
Aim 2 will investigate the consequences to the aging oxidizable proteome of this age-related loss of neuronal GSH, NADH and redox potential. As the final stage of epigenetic development, Aim 3 will examine the epigenetic controls for this age-related increase in susceptibility to stressor toxicity in old rats, including histone acetylation and CpG methylation of mitochondrial promoters. Since estrogen is neuroprotective to old neurons at pM concentrations, the ability of estrogen to reverse the changes observed in each aim will also be determined. Completion of the proposed studies should provide definitive evidence for a mechanistic basis of age-related stressor susceptibility and nutraceutical intervention.
The overall goal of the proposed work is to determine the mechanism of action of aging within mitochondria of neurons in the aging brain. Once specific targets are identified, then appropriate behavioral, nutraceutical or pharmacological proscriptions can be developed. These issues are critical to the aging population in the U.S. who will constitute 23% of the population in 2040, 70 million people. 13 million of these people are expected to have Alzheimer disease with expected health care costs of $250 billion.
