Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-0475, USA.
Nutritional Neuroscience (Impact Factor: 2.11). 10/2009; 12(5):203-18. DOI: 10.1179/147683009X423364
Source: PubMed

ABSTRACT The present study investigated the relationships among oxidative stress, beta-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F(4)-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.

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Available from: Michael P McDonald, Apr 01, 2015
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    • "zone surrounding the former platform location was used as a measure of memory during the probe trial. This zone score was used as a more accurate measure of memory, compared to quadrant time (Bernardo et al., 2007; Dhanushkodi and McDonald, 2011; Flanigan et al., 2014; Harrison et al., 2009a). Because of the shape of the pool quadrants, some locations within the target quadrant are farther away from the platform location than other locations in neighboring quadrants. "
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    ABSTRACT: Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7 months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r 2 = .959), but uncorrelated in transgenics (r 2 = .013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.
    Neurobiology of Disease 03/2015; 78:45-55. · 5.20 Impact Factor
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    • ", 2010 ; Ma et al . , 2009 ) seemed to elicit greater benefits than either alone on behavior and Ab deposition in the Tg2576 mouse . However , not all dietary combinations have proven beneficial . Coadministration of vitamins E and C to APP / PS1 mice resulted in spatial memory impairments that were not seen when vitamin C was administered alone ( Harrison et al . , 2009 ) . In a similar mouse model , combining DHA with phospholipid precursors exacerbated Ab deposition compared with either separately whereas coadministering both these com - pounds with additional micronutrients produced an anti - amyloidogenic effect ( Broersen et al . , 2013 ) . Combining DHA with a high saturated fat mixture appeared "
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    ABSTRACT: Food combinations have been associated with lower incidence of Alzheimer’s disease (AD). We hypothesized that a combination whole-food diet (WFD) containing freeze-dried fish, vegetables and fruits would improve cognitive function in TgCRND8 mice by modulating brain insulin-signaling and neuroinflammation. Cognitive function was assessed by a comprehensive battery of tasks adapted to the Morris water maze. Unexpectedly, a ‘Diet x Transgene’ interaction was observed in which transgenic animals fed the WFD exhibited even worse cognitive function than their transgenic counterparts fed the control diet on tests of spatial memory (P<0.01) and strategic rule learning (P=0.034). These behavioural deficits coincided with higher hippocampal gene expression of tumor necrosis factor-α (P=0.013). There were no differences in cortical amyloid-β peptide species according to diet. These results indicate that a dietary profile identified from epidemiological studies exacerbated cognitive dysfunction and neuroinflammation in a mouse model of familial AD. We suggest that normally adaptive cellular responses to dietary phytochemicals were impaired by amyloid-beta deposition leading to increased oxidative stress, neuroinflammation, and behavioural deficits.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.013 · 4.85 Impact Factor
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    • "Additionally, while vitamin E is a potent anti-oxidant, it forms reactive intermediate species that must be recycled to the active form and this process is limited by the availability of coantioxidants, including vitamins A and C (which are deficient in Alzheimer's disease) and ubiquinone. When coantioxidant molecules are deficient, the tocopheroxyl radical may paradoxically induce lipid peroxidation — an effect that has been demonstrated in a mouse model of Alzheimer's disease (Harrison et al., 2009). Subjects in treatment groups in both major trials were given 2000 international units α-tocopherol daily; for a frame of reference , the recommended dietary allowance is less than 25 IU/day for healthy adults. "
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    ABSTRACT: Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention.
    Neurobiology of Disease 07/2013; 59. DOI:10.1016/j.nbd.2013.07.005 · 5.20 Impact Factor
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