Oxidative stress may alter neuron function in the aged brain and contribute to age-related cognitive decline by altering communication within and between neurons. Understanding the neural manifestation of cognitive aging may lead to potential pharmacological therapies intended to attenuate age-related cognitive decline. The proposed research will directly examine the oxidative status of proteins specifically involved in neural signaling in the aged brain. Specifically, a second messenger system that is altered as a consequence of aging in both rats and humans is phosphoinositide (Pl) turnover. In aged rats, muscarinic and metabotropic glutamate receptor stimulation of PI turnover is blunted in the hippocampus, and is most blunted in aged rats with documented memory impairment. In these same rats, oxidative damage to hippocampal proteins has also been demonstrated, but the identity of these proteins has not been specified. The proposed experiments will attempt to identify the molecular site of PI turnover dysfunction that is associated with cognitive aging by examining the function and oxidative status of two signaling proteins coupled to PI turnover, Gq/11 and PLC-beta1. Using hippocampal tissue from young and aged rats that have been assessed for spatial learning ability, this project will address the following specific aims: 1) Do Gq/11 and PLC-beta1 maintain their ability to stimulate PI turnover in the hippocampus of aged rats with cognitive impairment? 2) Is muscarinic and metabotropic glutamate receptor coupling altered with age in the hippocampus, striatum and frontal cortex? 3) Are Gq/11 and PLC-beta1 oxidatively damaged in the hippocampus of the aged rat and does this damage correlate with cognitive impairment? 4) Can the age-related alterations that occur to Gq/11 and PLC-beta1 be replicated by experimentally inducing oxidative stress in the hippocampus of a young animal in vitro? If so, this model will subsequently be used to test the efficacy of antioxidants to prevent oxidative damage to Gq/11 and/or PLC-beta1 function. These studies have the potential to show the molecular site of age-related PI dysfunction, the cause of the dysfunction, and a linkage between oxidative damage to specific proteins and cognitive impairment.
Showing the most recent 10 out of 11 publications
