Beta-Amyloid Immunization in a Canine Model of Aging

  • Head, Elizabeth (PI)

Grants and Contracts Details


Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A~), which is thought to playa causative role in the disease. A number of therapeutic strategies are being developed that may reduce the production, deposition or enhance clearance ofA~ in the brains of patients with AD. We extended immunotherapy into the canine model of human brain aging, which naturally develops human-type A~ and serves as a model system for beta-amyloid pathogenesis. Using an active immunization procedure, we treated old dogs for 2 years (25 injections in total). Our results in immunized aged beagles showed a significant decrease in brain A~ and improvements and maintenance of executive function. We hypothesize that removing A~ would be of greater benefit to the brain if combined with approaches that can, in parallel, restore neuron function. Adding a behavioral enrichment component to immunization approaches may attenuate Ap associated neuron and cognitive dysfunction. To test this hypothesis, 2 aims are proposed in this study: Aim 1. Combining AI3 immunization with behavioral enrichment in aged dogs with pre-existing Aj3 pathology will lead to improved cognition. Aim 2. Combining Aj3 immunization with behavioral enrichment in aged dogs with pre-existing Aj3 pathology will lead to reduced AJ3and associated neuropathology. Studying cognition and brain pathology in aging dogs captures many of the key patterns of cognitive aging and brain pathology in normal brain aging. Further, the severity of cognitive dysfunction and the accumulation of neuropathology in canines suggest they may also approximate pathological aging observed in individuals with mild cognitive impairment (MC!). These characteristics of the model emphasizes the potential for translation of study results in the canine to human clinical trials and to further our understanding of molecular events leading to pathological aging in humans. The results of our studies to date are exciting, presenting multiple research opportunities in the underlying mechanisms and biological bases for improvements in cognition we have observed. Thus, our canine studies have tested hypotheses that are mechanistically driven and have the important feature of bemg directly translatable to humans. Further, our approach, of combining two treatments to determine if the effects are additive on cognitive outcomes and on neurobiological measures of pathology has been demonstrated to be a powerful approach to identify ways in which we can promote healthy brain aging in humans.
Effective start/end date3/1/092/28/15


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