Aβ vaccination in combination with behavioral enrichment in aged beagles: effects on cognition, Aβ, and microhemorrhages

Beta-amyloid (A beta) immunotherapy is a promising intervention to slow Alzheimer's disease. Aging dogs naturally accumulate A beta and show cognitive decline. An active vaccine against fibrillar A beta 1-42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain A beta. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in A beta. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11-12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); and (4) ENR/VAC (E/V) and treated for 20 months. VAC decreased brain A beta, pyroglutamate A beta, increased cerebrospinal fluid Ab 42 and brain-derived neurotrophic factor RNA levels but also increased microhemorrhages. ENR reduced brain A beta and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced A beta, and increased brain-derived neurotrophic factor mRNA despite increased microhemorrhages; however, there were no benefits to memory. These results suggest that the combination of immunotherapy with behavioral enrichment leads to cognitive maintenance associated with reduced neuropathology that may benefit people with Alzheimer's disease. (C) 2016 Elsevier Inc. All rights reserved.