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.
|Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54|
|Chen, Z L; Huang, R Q (2014) Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus. Neuroscience 271:64-76|
|Payne, Andrew J; Kaja, Simon; Naumchuk, Yuliya et al. (2014) Antioxidant drug therapy approaches for neuroprotection in chronic diseases of the retina. Int J Mol Sci 15:1865-86|
|Cunningham, Rebecca L; Singh, Meharvan; O'Bryant, Sid E et al. (2014) Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease. J Alzheimers Dis 40:563-73|
|Cherry, Brandon H; Sumien, Nathalie; Mallet, Robert T (2014) Neuronal injury from cardiac arrest: aging years in minutes. Age (Dordr) 36:9680|
|Kaja, Simon; Naumchuk, Yuliya; Grillo, Stephanie L et al. (2014) Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model. Vision Res 94:16-23|
|Petrone, Ashley B; Gatson, Joshua W; Simpkins, James W et al. (2014) Non-feminizing estrogens: a novel neuroprotective therapy. Mol Cell Endocrinol 389:40-7|
|Shetty, Ritu A; Ikonne, Uzoma S; Forster, Michael J et al. (2014) Coenzyme Q10 and ?-tocopherol reversed age-associated functional impairments in mice. Exp Gerontol 58:208-18|
|Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo et al. (2014) Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity. J Biol Chem 289:9340-51|
|Sohal, Rajindar S; Forster, Michael J (2014) Caloric restriction and the aging process: a critique. Free Radic Biol Med 73:366-82|
Showing the most recent 10 out of 122 publications