An important aspect of brain aging is the increased glutamate (Glu) release and accumulation in the extracellular space of neurons. Age-associated increases in extracellular Glu occur because of partial loss of activity of Glu transporters. Essentially all neurons in the central nervous system (CNS) are exposed to elevated extracellular Glu, yet not all brain regions suffer equally. The sensitivity of certain neurons to the toxic effects of Glu produced through Ca2+- and oxidative stress-mediated processes, increases with age. The reasons for differential vulnerability of certain neurons to Glu are still not known. Also, no animal model of age-associated increases in Glu release in CNS is available to determine how excess Glu produces its effect on aging neurons. We have generated transgenic (Tg) mice that have extra copies of the gene for Glu dehydrogenase 1 (GLUD1), a mitochondrial enzyme considered to be a rate-limiting, step in the biosynthesis of Glu as a transmitter. The GLUD1 transgene, introduced under the control of a neuron-specific promoter, is expressed only in neurons. GLUD1 mice have higher levels of depolarization-induced Glu release than wild type (wt) and suffer losses in specific neuronal populations. GLUD1 mice also have a shortened life span without exhibiting severe neurological dysfunction. The hypothesis being tested is that excess extracellular Glu in aging brain initiates events that lead to altered metabolic states in CNS, damage to select populations of neurons, an imbalance between damage and recovery, metabolic stress in peripheral tissues, and decreased longevity. Short-term objectives are: a) To quantify changes in longevity and protein/ DNA oxidation in brain and other tissues of hyper-glutamatergic and wt mice;b) To determine changes in metabolism, gene expression, and morphology of vulnerable and resistant neurons;and c) To characterize a signaling protein complex involved in active neurite remodeling and define how Glu hyperactivity and aging affect this complex. The long-term objectives are to understand the molecular and cellular processes that link increased Glu activity in CNS to age-dependent changes in neuronal structure and function, but without neurological disease, and to identify potential targets for therapeutic intervention. To test the hypothesis, we developed the following specific aims: 1) Assess longevity and protein and DNA oxidation levels in brain and other tissues of wt and Tg mice during aging;2) Determine the effects of neuronal GLUD1 overexpression and of aging on structural, metabolic and gene expression changes in vulnerable and resistant neurons;and 3) Determine the age-dependent changes in expression, composition and activity of a Ca2+-sensitive, dendrite-growth controlling complex in GLUD1 and wt mice. These studies make use of a novel animal model of age-associated hyperglutamatergic states to probe mechanisms of differential neuronal vulnerability and novel molecular mechanisms of neuronal recovery from stress.

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National Institute on Aging (NIA)
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University of Kansas Lawrence
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Poole, Leslie B; Schöneich, Christian (2015) Introduction: What we do and do not know regarding redox processes of thiols in signaling pathways. Free Radic Biol Med 80:145-7
Nauser, Thomas; Koppenol, Willem H; Schöneich, Christian (2015) Protein thiyl radical reactions and product formation: a kinetic simulation. Free Radic Biol Med 80:158-63
Badawi, Yomna; Pal, Ranu; Hui, Dongwei et al. (2015) Ischemic tolerance in an in vivo model of glutamate preconditioning. J Neurosci Res 93:623-32
Wang, Xinkun; Patel, Nilam D; Hui, Dongwei et al. (2014) Gene expression patterns in the hippocampus during the development and aging of Glud1 (Glutamate Dehydrogenase 1) transgenic and wild type mice. BMC Neurosci 15:37
Jiang, Lei; Bechtel, Misty D; Bean, Jennifer L et al. (2014) Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase. Biochim Biophys Acta 1838:1255-65
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Choi, In-Young; Lee, Phil; Wang, Wen-Tung et al. (2014) Metabolism changes during aging in the hippocampus and striatum of glud1 (glutamate dehydrogenase 1) transgenic mice. Neurochem Res 39:446-55

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