Synergistic Effects of Long-Term Antioxidant Diet and Behavioral Enrichment on -Amyloid Load and Non-Amyloidogenic Processing in Aged Canines

Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697-4540, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2010; 30(29):9831-9. DOI: 10.1523/JNEUROSCI.6194-09.2010
Source: PubMed

ABSTRACT A long-term intervention (2.69 years) with an antioxidant diet, behavioral enrichment, or the combined treatment preserved and improved cognitive function in aged canines. Although each intervention alone provided cognitive benefits, the combination treatment was additive. We evaluate the hypothesis that antioxidants, enrichment, or the combination intervention reduces age-related beta-amyloid (Abeta) neuropathology, as one mechanism mediating observed functional improvements. Measures assessed were Abeta neuropathology in plaques, biochemically extractable Abeta(40) and Abeta(42) species, soluble oligomeric forms of Abeta, and various proteins in the beta-amyloid precursor protein (APP) processing pathway. The strongest and most consistent effects on Abeta pathology were observed in animals receiving the combined antioxidant and enrichment treatment. Specifically, Abeta plaque load was significantly decreased in several brain regions, soluble Abeta(42) was decreased selectively in the frontal cortex, and a trend for lower Abeta oligomer levels was found in the parietal cortex. Reductions in Abeta may be related to shifted APP processing toward the non-amyloidogenic pathway, because alpha-secretase enzymatic activity was increased in the absence of changes in beta-secretase activity. Although enrichment alone had no significant effects on Abeta, reduced Abeta load and plaque maturation occurred in animals receiving antioxidants as a component of treatment. Abeta measures did not correlate with cognitive performance on any of the six tasks assessed, suggesting that modulation of Abeta alone may be a relatively minor mechanism mediating cognitive benefits of the interventions. Overall, the data indicate that multidomain treatments may be a valuable intervention strategy to reduce neuropathology and improve cognitive function in humans.

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    • "Treatment with an antioxidant diet and behavioral enrichment resulted in improved performance during black and white object discrimination and reversal (Milgram et al., 2005). Pop et al. (2010b) found dogs provided with both behavioral enrichment and an antioxidant diet have an overall reduction in Aβ pathology across multiple regions of the brain. However, when looking at group treatment effects, only the antioxidant-treated animals had a significant reduction in Aβ plaque pathology. "
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    ABSTRACT: Aged dogs spontaneously develop many features of human aging and Alzheimer's disease (AD) including cognitive decline and neuropathology. In this review, we discuss age-dependent learning tasks, memory tasks, and functional measures that can be used in aged dogs for sensitive treatment outcome measures. Neuropathology that is linked to cognitive decline is described along with examples of treatment studies that show reduced neuropathology in aging dogs (dietary manipulations, behavioral enrichment, immunotherapy, and statins). Studies in canine show that multi-targeted approaches may be more beneficial than single pathway manipulations (e.g., antioxidants combined with behavioral enrichment). Aging canine studies show good predictive validity for human clinical trials outcomes (e.g., immunotherapy) and several interventions tested in dogs strongly support a prevention approach (e.g., immunotherapy and statins). Further, dogs are ideally suited for prevention studies as they the age because onset of cognitive decline and neuropathology strongly support longitudinal interventions that can be completed within a 3-5 year period. Disadvantages to using the canine model are that they lengthy, use labor-intensive comprehensive cognitive testing, and involve costly housing (almost as high as that of non-human primates). However, overall, using the dog as a preclinical model for testing preventive approaches for AD may complement work in rodents and non-human primates.
    Frontiers in Pharmacology 03/2014; 5:47. DOI:10.3389/fphar.2014.00047 · 3.80 Impact Factor
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    • "For example, small bouts of environmental enrichment have important genetic effects on developing mice (Arai & Feig 2010). In addition, behavioral enrichment decreases β-amyloid load in several brain regions of aging laboratory beagle dogs and protects against cognitive decline associated with aging (Christie et al. 2009; Cotman & Head 2008; Pop et al. 2010). In considering the possible implications of these results for the human case, however, it is not clear to what extent these findings may be a product of the deprived conditions offered by the laboratory. "
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    ABSTRACT: We review a range of studies on the genetic contribution to behavior in canid species. We begin by identifying factors that make canids a promising model in behavioral genetics and proceed to review research over the last decade that has used canids to identify genetic contributions to behavior. We first review studies that have selectively bred dogs to identify genetic contributions to behavior and then review studies that estimate heritability from populations of non-laboratory bred dogs. We subsequently review studies that used molecular genetics to identify gene-behavior associations and note associations that have been uncovered. We then note challenges in canid behavioral genetics research that require further consideration. We finish by suggesting alternative phenotyping methods and identify areas in which canids may have as yet unexploited advantages, such as in gene-environment interaction studies where genetic factors are found to moderate the effects of environmental variables.
    Genes Brain and Behavior 09/2012; 11(8). DOI:10.1111/j.1601-183X.2012.00851.x · 3.66 Impact Factor
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    • "The reduction in oxidative damage correlated with cognitive improvement [9], suggesting that accumulating oxidative stress is likely to be a central feature underlying cognitive decline in aging. In parallel with reducing oxidative damage, the behavioral and dietary interventions modestly reduced the accumulation of Aβ in the aged canine brain, particularly with the combined intervention [10]. Surprisingly, while Aβ load was reduced in entorhinal, cingulate and parietal cortices, improvements in cognitive performance did not correlate with Aβ load [10], suggesting that effects on Aβ are likely not a central mechanism underlying the cognitive benefits of the interventions. "
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    ABSTRACT: Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aβ accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aβ, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON--control environment/control diet, AOX--control environment/antioxidant diet, ENR--enriched environment/control diet, AOX/ENR--enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging.
    PLoS ONE 09/2011; 6(9):e24652. DOI:10.1371/journal.pone.0024652 · 3.23 Impact Factor
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