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


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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    • "The combination of an antioxidant-fortified diet and environmental enrichment reduced age-related cognitive impairment and increased BDNF levels in dogs more than did either treatment alone (Fahnestock et al., 2012). Beneficial interactions between combinations of dietary supplementation and environmental enrichment or exercise have also been observed in investigations of Alzheimer's disease (Pop et al., 2010) and synaptic plasticity (Wu et al., 2008). Although environmental enrichment and exercise affect neurogenesis via distinct pathways (neuronal survival and proliferation respectively; Olson et al., 2006), they are difficult to dissociate experimentally because environmental enrichment protocols typically have an exercise component. "
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    ABSTRACT: Chronic stress has a profoundly negative impact on the brain (1). Even acute stress exposure can markedly decrease neurogenesis (2), with significant implications for plasticity, memory, and mood (3). It is evident that the heightened plasticity of these newborn neurons makes them responsive to many environmental factors, which consequently affect behaviour. Some factors that robustly enhance neurogenesis and can mitigate the effects of stress and depression include antidepressant medications (4), dietary antioxidants (5) and exercise (6). At the physiological level, these factors are associated with biochemical processes and signaling pathways which are also altered in age-related cognitive decline, such as neurotrophin expression (7), cellular oxidative stress (5), inflammation (8) and mTOR regulation (9). A complex dietary supplement designed to counteract five potential mechanisms of ageing: inflammation, oxidative stress, mitochondrial dysfunction, insulin resistance and membrane integrity, has been shown to ameliorate physiological and cognitive decline in aged transgenic growth hormone mice (an accelerated aging model) and aged wild type control mice (10). We therefore predicted that this supplement combined with aerobic exercise would exert potent neuroprotective effects against chronic unpredictable stress in young adult mice. Four weeks of unpredictable mild stress strongly affected all stressed groups, as indicated by reduced saccharin preference and increased adrenal weights. Interestingly, the combination of dietary supplementation and aerobic exercise buffered the adverse effects of stress, as reflected in the number of doublecortin-positive immature neurons in the dentate gyrus, the sectional area of the dentate gyrus and CA1, and serum vascular endothelial growth factor levels. In contrast, these benefits were not observed in chronically stressed animals exposed to dietary supplementation or exercise alone. It is expected that RT-PCR analysis of hippocampal brain-derived neurotrophic factor mRNA, currently under investigation using samples from these animals, will reveal a similar pattern. Given the well-established effects of aerobic exercise (6) on neurogenesis in non-stressed animals, it is interesting that in stressed animals we observed no such benefit of either exercise or dietary supplementation alone, whereas the combination of diet supplementation and exercise exerted potent neuroprotective effects on hippocampal integrity. Our findings have important clinical implications for those suffering chronic stress-related psychiatric disorders such as major depression. (1) Gould, E.; McEwen, B. S.; Tanapat, P.; Galea, L. A.; Fuchs, E. J. Neurosci. 1997, 17, 2492–2498. (2) Gould, E.; Cameron, H. A.; Daniels, D. C.; Woolley, C. S.; McEwen, B. S. J. Neurosci. 1992, 12, 3642–3650. (3) Willner, P.; Towell, A.; Sampson, D.; Sophokleous, S.; Muscat, R. Psychopharmacology (Berl). 1987, 93, 358–364. (4) Malberg, J. E.; Eisch, A J.; Nestler, E. J.; Duman, R. S. J. Neurosci. 2000, 20, 9104–9110. (5) Valente, T.; Hidalgo, J.; Bolea, I.; Ramirez, B.; Anglés, N.; Reguant, J.; Morelló, J. R.; Gutiérrez, C.; Boada, M.; Unzeta, M. J. Alzheimers. Dis. 2009, 18, 849–865. (6) van Praag, H.; Kempermann, G.; Gage, F. H. Nat. Neurosci. 1999, 2, 266–270. (7) Sairanen, M.; Lucas, G.; Ernfors, P.; Castrén, M.; Castrén, E. J. Neurosci. 2005, 25, 1089–1094. (8) Goshen, I.; Kreisel, T.; Ben-Menachem-Zidon, O.; Licht, T.; Weidenfeld, J.; Ben-Hur, T.; Yirmiya, R. Mol. Psychiatry 2008, 13, 717–728. (9) Ota, K. T.; Liu, R.; Voleti, B.; Maldonado-Aviles, J. G.; Duric, V.; Iwata, M.; Dutheil, S.; Duman, C.; Boikess, S.; Lewis, D. A.; Stockmeier, C. A.; DiLeone, R. J.; Rex, C.; Aghajanian, G. K.; Duman, R. S. Nat. Med. 2014, 20, 531–535. (10) Aksenov, V.; Long, J.; Liu, J.; Szechtman, H.; Khanna, P.; Matravadia, S.; Rollo, C. D. Age (Dordr). 2013, 35, 23–33.
    Adult Neurogenesis: Evolution, Regulation and Function, Center for Regenerative Therapies, Dresden, Germany; 05/2015
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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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