Alzheimer's disease (AD) is manifested by progressive memory loss and cognitive deterioration. The pathological hallmarks of the disease include neuronal loss and the deposition of p-amyloid peptides (AP) in specific brain areas, including the cortex and hippocampus. Compelling evidence has accrued to suggest that the cortex and the hippocampus exhibit environment-induced plasticity throughout adult life. Exposure of rodents to an "enriched environment" has been shown to have numerous beneficial effects, including: enhancement of learning and memory;protection from age-associated cognitive decline;increased neurogenesis;and upregulation of neurotrophic factors and immediate-early genes (IEG) associated with learning and memory. We have tested the hypothesis that environmental conditions might play a role in modulating hippocampal plasticity in a manner that impact on amyloid deposition. We reported that amyloid deposition and steady-state levels of AP peptides are markedly reduced in brains of transgenic mice exposed to enriched environment conditions, compared to mice that were maintained in standard housing conditions (Lazarov et al., 2005). Moreover, we observed an inverse correlation between the level of physical activity and the extent of amyloid deposition. We established that the activity of neprilysin, a zinc metallopeptidase known to be involved in AP degradation in vivo, is elevated in the brains of mice exposed to the enriched environment. Finally, high density oligonucleotide arrays revealed upregulation of genes associated with vasculogenesis, neurogenesis, AP sequestration and learning and memory processes. Encouraged by these provocative findings, we now propose a series of experiments to further explore the effect of environmental conditions on AD-related processes in the brains of transgenic mice. In Specific Aim 1 we will isolate the stimulus involved in enriched- mediated modulation of AP peptide accumulation and deposition and assess the effects on the transcriptome and APR processing in vivo. In Specific Aim 2 we will ask whether reduced expression of selected genes identified in our microarray analyses will affect histological and biochemical endpoints in the brains of mice following enrichment. In Specific Aim 3 we will examine the role of enrichment on the cerebrovasculature and hippocampal neurogenesis of these animals. In summary, our research program is designed to provide a molecular, cellular and physiological framework for understanding the mechanism(s) by which environmental enrichment modulates amyloid deposition in transgenic mice. These efforts will provide valuable new information relevant to defining new preventative measures and therapeutic strategies for Alzheimer's disease.