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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020572-04
Application #
7117330
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Wise, Bradley C
Project Start
2003-06-01
Project End
2007-05-31
Budget Start
2006-07-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$245,223
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
McQuail, Joseph A; Nicolle, Michelle M (2015) Spatial reference memory in normal aging Fischer 344 × Brown Norway F1 hybrid rats. Neurobiol Aging 36:323-33
McQuail, Joseph A; Davis, Kathleen N; Miller, Frances et al. (2013) Hippocampal G?q/?? but not G?o-coupled receptors are altered in aging. Neuropharmacology 70:63-73
McQuail, Joseph A; Banuelos, Cristina; LaSarge, Candi L et al. (2012) GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats. Neurobiol Aging 33:1124.e1-12
Nieves-Martinez, Erasmo; Haynes, Kathryn; Childers, Steven R et al. (2012) Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats. Behav Brain Res 227:258-64
Sergeant, Susan; McQuail, Joseph A; Riddle, David R et al. (2011) Dietary fish oil modestly attenuates the effect of age on diastolic function but has no effect on memory or brain inflammation in aged rats. J Gerontol A Biol Sci Med Sci 66:521-33
McQuail, Joseph A; Riddle, David R; Nicolle, Michelle M (2011) Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain. Neurobiol Aging 32:2322.e1-4
Nieves-Martinez, E; Sonntag, W E; Wilson, A et al. (2010) Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation. J Endocrinol 204:31-6
Mitschelen, M; Garteiser, P; Carnes, B A et al. (2009) Basal and hypercapnia-altered cerebrovascular perfusion predict mild cognitive impairment in aging rodents. Neuroscience 164:918-28
Zhang, Hai-Yan; Watson, Mona L; Gallagher, Michela et al. (2007) Muscarinic receptor-mediated GTP-Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats. Neurobiol Aging 28:619-26
Shi, Lei; Adams, Michelle M; Long, Ashley et al. (2006) Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat Res 166:892-9

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