Elsevier

Neurobiology of Aging

Volume 23, Issue 5, September–October 2002, Pages 809-818
Neurobiology of Aging

Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction

https://doi.org/10.1016/S0197-4580(02)00073-8Get rights and content

Abstract

Animal models that simulate various aspects of human brain aging are an essential step in the development of interventions to manage cognitive dysfunction in the elderly. Over the past several years we have been studying cognition and neuropathology in the aged-canine (dog). Like humans, canines naturally accumulate deposits of β-amyloid (Aβ) in the brain with age. Further, canines and humans share the same Aβ sequence and also first show deposits of the longer Aβ1–42 species followed by the deposition of Aβ1–40. Aged canines like humans also show increased oxidative damage. As a function of age, canines show impaired learning and memory on tasks similar to those used in aged primates and humans. The extent of Aβ deposition correlates with the severity of cognitive dysfunction in canines. To test the hypothesis that a cascade of mechanisms centered on oxidative damage and Aβ results in cognitive dysfunction we have evaluated the cognitive effects of an antioxidant diet in aged canines. The diet resulted in a significant improvement in the ability of aged but not young animals to acquire progressively more difficult learning tasks (e.g. oddity discrimination learning). The canine represent a higher animal model to study the earliest declines in the cognitive continuum that includes age associated memory impairments (AAMI) and mild cognitive impairment (MCI) observed in human aging. Thus, studies in the canine model suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements, supporting the need for further human studies.

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

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