Prevention approaches in a preclinical canine model of Alzheimer's disease: benefits and challenges

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.

Keywords: antioxidant diet; atorvastatin; behavioral enrichment; beta-amyloid; combination treatment; dog; immunotherapy; statin.

FIGURE 1

Immunoreactivity for Aβ 1-42 in frontal cortex brain tissue of (A) an aged canine and (B) an aged human. Compact Aβ deposits are similar in humans and canines (arrow head). The outline of an intact neuron enveloped by a diffuse plaque is visible (arrow). Aβ 1-40 immunoreactivity of cerebral amyloid angiopathy is similar in aged canine occipital cortex (C) and aged human occipital cortex (D). Reproduced from Martin et al. (2011b).