Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction
Introduction
The brain progressively accumulates oxidative damage and other types of neuropathology that ultimately result in neuronal dysfunction and cognitive decline. A key challenge is to identify mechanisms underlying pathological aging and to develop therapeutics to prevent or slow disease progression. Animal models, including rodents and nonhuman primates, are critical to the success of this research. Over the past several years we have been investigating a novel animal model of human cognitive aging, the aged canine. The advantages of using canines to study brain aging includes the following: (1) canines share many of the same environmental conditions with humans; (2) canines can perform a sophisticated repertoire of complex cognitive behaviors; (3) the brain in aged canines shows many pathological changes common to humans; and (4) neuropathology is significantly associated with cognitive decline.
Our strategy has been to identify brain and behavioral changes that appear with age and to determine if interventions that target proposed underlying cellular pathological mechanisms can improve cognitive function. The proof of principle to determine whether a specific type of neuropathology contributes to cognitive dysfunction is to show that an intervention targeting the proposed mechanism improves function. Of necessity, studies in humans are primarily correlative but help to establish key pathological mechanisms amenable to manipulation. Over time these studies may lead to clinical trials but even if successful it is difficult to determine if the intervention has an effect on brain pathology. In the canine model it is feasible to test interventions and determine the effect they have on the brain. In this review we present an overview of the progress in characterizing the canine model and the effects of antioxidants on cognitive function. The review has three parts: (1) an overview of neuropathology in the aged canine brain; (2) the nature of cognitive dysfunction in the aged canine; and (3) recent results demonstrating the effectiveness of an antioxidant intervention in improving cognitive performance on select tasks that decline with age.
Section snippets
Neuropathological features of the aged canine brain
A critical issue is to identify neuropathology that has the greatest functional impact on cognitive decline. The canine brain exhibits several key features observed in the aged human brain. Many of these consistent features are associated with early pathology seen in normal human brain aging, in the brains of individuals with mild cognitive impairment (MCI) and in Alzheimer’s disease (AD) patients. In the canine, these features do not develop into the full-blown pathology associated with
Cognitive dysfunction in aged canines
The advanced learning ability of canines is well known, as evidenced by their use as guides for the blind and as military working dogs. Our research has focused on a single breed, beagles, because longevity varies widely with respect to breed as does the age of onset and extent of Aβ [6]. The average life span of a beagle is 13.6 years but animals that live up to 18 years have been observed [67]. Beagles over the age of 8 years are considered old based upon evidence for reduced cerebrovascular
Relationship between age, pathology and behavior in aged canines
Is cognitive dysfunction associated with Aβ neuropathology? Several studies demonstrate a strong and significant association between the extent of Aβ deposition and the extent of cognitive dysfunction in dogs [16], [17], [32] similar to that reported in the human brain [15] (Fig. 2). This association can be further refined on a brain region basis: for example, Aβ in the prefrontal cortex is correlated with frontal-dependent learning and memory deficits [32]. A recent paper by Colle et al.
Oxidative damage and brain aging
The brain has among the highest respiratory rate of any tissue and generates oxidative damage that progressively increases over time [2]. Neurons, are particularly vulnerable to cumulative oxidative damage because they are nondividing cells and survive for decades. The generation of oxidants leads to damage to proteins, lipids and nucleotides, which may contribute significantly to neuron dysfunction and degeneration associated with aging and neurodegenerative diseases [25], [48]. Oxidative
An antioxidant diet improves learning in the aged canine
Accordingly, we have initiated a series of studies to test the hypothesis that an antioxidant diet can result in improvements in learning and memory and reduce the extent of pathology that accumulates in the aged brain [55]. We have collected extensive data in an ongoing study on learning and memory with treatment but results of the neuropathology studies are not available at present. The study is being conducted as a random placebo controlled clinical trial. The study involves the selection of
Conclusions
Aged canines, like humans develop age-related neuropathologies, particularly the accumulation of Aβ, develop impaired cognitive function. We hypothesize that cognitive function in canines declines along a “cognitive continuum” that reflects a similar phenomenon in humans [61]. In humans, the continuum is postulated to begin with the development of age associated memory impairment (AAMI) defined as a loss in memory on one or more tests that is 1 S.D. below that of the young population normative
Acknowledgements
This project was sponsored by funds provided by the National Institute of Aging (Grant AG12694), the US Department of the Army, Contract No. DAMD17-98-1-8622, and by Hill’s Pet Nutrition, Inc. Topeka, KS. The content of the information does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred. The investigators adhered to the “Guide for the Care and Use of Laboratory Animals” prepared by the Committee on Care and Use of Laboratory
References (81)
- et al.
Spatial learning and memory in the dog as a model of cognitive aging
Behav. Brain Res.
(2000) - et al.
DNA damage and apoptosis in the aged canine brain: relationship to Aβ deposition in the absence of neuritic pathology
Prog. Neuropsychopharmacol. Biol. Psychiatr.
(2000) - et al.
Paucity of morphological changes in the brains of ageing beagle dogs: further evidence that Alzheimer lesions are unique for primate central nervous system
Neurobiol. Aging
(1983) Alzheimer’s disease and oxidative stress: implications for novel therapeutic approaches
Prog. Neurobiol.
(1999)- et al.
Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide
Trends Mol. Med.
(2001) - et al.
Development of a protocol for studying object recognition memory in the dog
Prog. Neuropsychopharmacol. Biol. Psychiatr.
(2000) - et al.
Vascular and parenchymal Aβ deposition in the aging dog: correlation with behavior
Neurobiol. Aging
(2000) - et al.
Beta-amyloid “load” correlates with severity of Alzheimer’s dementia: quantification via image analysis
Lancet
(1995) - et al.
Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine
Neurobiol. Learn. Mem.
(1996) - et al.
Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs
Neurobiol. Aging
(1996)