Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents

Nicolle, Michelle M.; Gonzalez, John; Sugaya, Kimio; Baskerville, Karen A.; Bryan, David R.; Lund, Kelli C.; Gallagher, Michela; McKinney, Michael

doi:10.1016/s0306-4522(01)00374-8

Cited by 160 publications

(98 citation statements)

References 48 publications

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“…Dubey et al (1996) reported age-related increases in protein oxidation in several regions of the forebrain, most notably in the hippocampus and striatum, whereas no change was observed in the brainstem. Such oxidative damage to proteins would seem to have functional implications, as suggested by the correlation of the severity of the damage with cognitive or motor performance of aged mice or rats Nicolle et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

2007

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The main purpose of the present study was to determine whether specific regions of the mouse brain exhibit different age-related changes in oxidative stress, as indicated by glutathione redox state and the level of protein-glutathionyl mixed disulfides. Comparison of 3-and 21-month-old mice indicated an age-related decrease in the ratio of reduced to oxidized glutathione (GSH:GSSG) as well as a prooxidizing shift in the calculated redox potential (ranging from 6 to 15 mV) in the cortex, hippocampus, striatum and cerebellum, whereas there was little change in the brainstem. This pro-oxidizing shift in redox state was due to a modest decrease in GSH content occurring in all the brain regions examined, and elevations in GSSG amount that were most pronounced in the striatum and cerebellum. The regional changes in glutathione redox state were paralleled by increases in the amounts of protein-mixed disulfides. A reduction of caloric intake by 40% for a short period (7 weeks), implemented in relatively old mice (17 months), increased the GSH:GSSG ratio and redox potential at 19 months in the same brain regions that exhibited age-related decreases. The effects of age and caloric restriction were qualitatively similar in C57BL/6 and DBA/2 mice. However, young DBA/2 mice, which do not show extension of life span in response to long-term caloric restriction, had lower GSH:GSSG ratios and higher protein-mixed disulfides than age-matched C57BL/6 mice. The current findings demonstrate that oxidative stress, as reflected by glutathione redox state, increases in the aging brain in regions linked to age-associated losses of function and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

2007

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“…Several biological processes have been associated with normal brain aging and neurodegenerative conditions, including inflammatory responses (Rogers et al, 1996;Murray and Lynch, 1998;Hauss-Wegrzyniak et al, 2000;Andreasson et al, 2001;Finch et al, 2002;Gemma et al, 2002;Wyss-Coray and Mucke, 2002), oxidative stress (Carney et al, 1991;Butterfield et al, 1999;Bickford et al, 2000;Nicolle et al, 2001;Wang et al, 2001), reduced mitochondrial function (Nicotera and Orrenius, 1998;Wallace, 2001), and altered Ca 2ϩ regulation (Landfield and Pitler, 1984;Michaelis et al, 1984;Gibson and Peterson, 1987;Khachaturian, 1989;Disterhoft et al, 1993;Franklin and Johnson, 1994;Lipton and Rosenberg, 1994;Foster and Norris, 1997;Nicotera and Orrenius, 1998;Verkhratsky and Toescu, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…The triggers and consequences of these putative brain aging mechanisms are not well understood, although several are accompanied by altered gene expression (Rogers et al, 1996;Finch and Tanzi, 1997;Chen et al, 2000;Lee et al, 2000;Nicolle et al, 2001). Moreover, specific gene mutations are directly involved in age-dependent neurodegenerative disease (for review, see Price and Sisodia, 1998;Selkoe, 2001;Tanzi and Bertram, 2001).…”

Section: Introductionmentioning

confidence: 99%

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

et al. 2003

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Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n ϭ 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging-and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca 2ϩ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce agingrelated cognitive impairment.

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“…Age-related accumulation of oxidative damage in brain contributes to cognitive deterioration (Nicolle et al 2001;Dröge and Schipper 2007;Rollo 2009), but recently, energy metabolism (i.e., age-related decline in mitochondrial function) has also been highlighted (Navarro and Boveris 2007;Aksenov et al 2010). Mitochondrial complex I dysfunction is strongly implicated in PD (Navarro and Boveris 2009), and complex III is also associated with generation of reactive oxygen species (ROS) relevant to aging (Chen et al 2004;Muller et al 2004).…”

Section: Introductionmentioning

confidence: 99%

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

Aksenov

Long

Liu

et al. 2011

AGE

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We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

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Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents

Cited by 160 publications

References 48 publications

Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

Effects of age and caloric intake on glutathione redox state in different brain regions of C57BL/6 and DBA/2 mice

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

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