Dissecting Out the Contribution of Cognitive, Social, and Physical Activities to Environmental Enrichment’s Ability to Protect Alzheimer’s Mice Against Cognitive Impairment

Retrospective studies suggest that lifestyle activities may provide protection against Alzheimer s Disease (AD). However, such studies can be inaccurate and prospective longitudinal studies investigating lifestyle protection against AD are both impractical and impossible to control for. Transgenic (Tg+) AD mice offer a model in a well controlled environment for testing the potential for environmental factors to impact AD development. In an initial study, Tg+ and non-transgenic (Tg-) mice were housed in either environmentally enriched (EE) or standard housing (SH) from 2-6 months of age, with a behavioral battery given during the last 5 weeks of housing. In the Morris maze, platform recognition, and radial arm water maze tasks, Tg+/EE mice were completely protected from cognitive impairment present in Tg+/SH mice and comparable to control Tg-/SH mice in cognitive performance. The current study utilized the same cognitivebased behavioral battery and multimetric statistical analysis to investigate the protective effects of “complete” environment enrichment (EE) versus several of its components (physical activity, social interactions) in AD transgenic mice. The AD transgenic mice utilized develop beta-amyloid (Aβ) deposition and cognitive impairment by 6-7 months of age. Similar to our initial study, results show that “complete” EE (physical, social, and cognitive activities) from 2 to 8 months of age completely protected AD transgenic mice from cognitive impairment in tasks representing different cognitive domains − working memory, reference learning, and search/recognition. In strong contrast, Tg+ mice reared in environments that included physical activity and social interaction, or only social interaction, were not protected from cognitive impairment in adulthood – enhanced cognitive activity was required over and above that present in these other environments. Through use of discriminant function analysis, EE and/or NT mice were consistently discriminated from the poorer performing other housing groups. The cognitive benefits observed in EE-housed Tg+ mice occurred without significant changes in cortical Aβ levels, plasma cytokine levels, or plasma corticosterone levels, suggesting involvement of mechanisms independent of these endpoints. However, EE-housed Tg+ mice did have decreased dendritic length of neurons in the parietal cortex (but not hippocampus). Noteworthy is that plasma cytokine levels and hippocampal dendritic length consistently correlated with cognitive measures, suggesting their involvement in underlying mechanisms of cognitive performance. The present work provides the first evidence that “complete” EE (including enhanced cognitive activity) is needed to provide cognitive protection against AD in a Tg+ model of the disease, while the physical and social activity components of EE do not alone lead to protection. These results suggest that humans desiring to gain maximal environmental protection against AD should live a lifestyle high in cognitive, social, and physical activities together