The ability of reactive oxygen species (ROS) to produce dysfunctional macromolecules is thought to play a significant role in brain aging and in neurodegenerative diseases. However, it is also well established that ROS serve as important signaling molecules involved in cellular processes that underlie different cognitive functions. In the current application, it is hypothesized that age-dependent increases in ROS may cause age- associated cognitive or motor impairment by (i) promoting deleterious accumulation of oxidative damage to specific mitochondrial proteins, (ii)causing a decrease in efficiency of ROS-mediated signaling and/or(iii) initiating compensatory shifts in signaling mechanisms underlying brain processes.
Under Aim 1 of this application, we will identify proteins in mitochondria from different brain regions that are associated with age- related increases in carbonyls, in aged mice with and without cognitive or motor impairments. The functional significance of these impairment-associated oxidized proteins will be addressed further under Aim 2, in which it is proposed to determine the correlation between impaired bioenergetic activity of oxidized proteins and age-related behavioral dysfunction.
Aim 3 of this application will assess whether or not the age-related increase in """"""""unregulated ROS"""""""" contributes to impairment of synaptic plasticity and memory function, and assess whether or not this contribution is age-dependent.
Aim 4 of the application is to determine if behavioral impairments associatedwith ROS can be reversed by experimental interventions that produce reductive shifts in the redox state of glutathione, or promote recovery of bioenergetic functions of specific oxidized proteins.
The Aim 4 studies will also address whether or not the ability of interventions to reverse age-related impairments is age-dependent. The results of these studies should refute or validate the idea that oxidative damage to specific mitochondrial proteins is a factor in age-related decrements in cognitive or psychomotor performance, and may identify specific molecules that should be targeted by anti-aging interventions. These studies will also address the hypothesis that increases in unregulated ROS directly impair cognition during aging and promote relatively non-reversible derangement of underlying signaling processes. Finally, these studies will identify periods of senescence for which antioxidative treatment of cognitive decline is most likely to be successful.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-8)
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West Virginia University
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Sun, Jiahong; Ren, Xuefang; Qi, Wen et al. (2016) Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the 'Neuronal Warburg Effect'. J Ethnopharmacol 187:249-58
Engler-Chiurazzi, E B; Singh, M; Simpkins, J W (2016) From the 90's to now: A brief historical perspective on more than two decades of estrogen neuroprotection. Brain Res 1633:96-100
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2016) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol :
Engler-Chiurazzi, Elizabeth B; Covey, Douglas F; Simpkins, James W (2016) A novel mechanism of non-feminizing estrogens in neuroprotection. Exp Gerontol :
Sarkar, S; Jun, S; Rellick, S et al. (2016) Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139-51
Richter, Frank; Koulen, Peter; Kaja, Simon (2016) N-Palmitoylethanolamine Prevents the Run-down of Amplitudes in Cortical Spreading Depression Possibly Implicating Proinflammatory Cytokine Release. Sci Rep 6:23481
Engler-Chiurazzi, Elizabeth B; Stapleton, Phoebe A; Stalnaker, Jessica J et al. (2016) Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition. J Toxicol Environ Health A 79:447-52
Sun, Fen; Nguyen, Trinh; Jin, Xin et al. (2016) Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk. Endocrinology 157:2067-79
Sun, Jiahong; Hu, Heng; Ren, Xuefang et al. (2016) Tert-butylhydroquinone compromises survival in murine experimental stroke. Neurotoxicol Teratol 54:15-21
Shetty, Ritu A; Rutledge, Margaret A; Forster, Michael J (2016) Retrograde conditioning of place preference and motor activity with cocaine in mice. Psychopharmacology (Berl) :

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