Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice

Abstract

Cerebral deposition of beta-amyloid (Abeta) peptides is an invariant pathological hallmark in brains of patients with Alzheimer's disease (AD) and transgenic mice coexpressing familial AD-linked APP and PS1 variants. We now report that exposure of transgenic mice to an "enriched environment" results in pronounced reductions in cerebral Abeta levels and amyloid deposits, compared to animals raised under "standard housing" conditions. The enzymatic activity of an Abeta-degrading endopeptidase, neprilysin, is elevated in the brains of "enriched" mice and inversely correlated with amyloid burden. Moreover, DNA microarray analysis revealed selective upregulation in levels of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, Abeta sequestration, and prostaglandin synthesis. These studies provide evidence that environmental enrichment leads to reductions in steady-state levels of cerebral Abeta peptides and amyloid deposition and selective upregulation in levels of specific transcripts in brains of transgenic mice.

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

“…First, a number of the IEGs (ARC, EGR1, EGR2, FOS, DUSP1, DUSP6) showed robust decreases in both adult and embryonic KO animals. In contrast, upregulation of BDNF by exercise 25,40,41 or by other in vitro manipulations leads to induction of these genes. 48 IEG induction is known to be strongly regulated via the MEK-ERK pathway, 49,50 which is also one of the main effectors of BDNF signaling.…”

“…[23][24][25] Briefly, microarrays were randomly mixed into two groups containing near equal numbers of experimental and control arrays (see Supplementary Figure 1). Six random permutations were performed with a blocking factor of mouse type (e.g., embryonic or adult deletion).…”

“…31,95,[97][98][99][100] In addition, APPswe/PS1dE9 amyloid plaque producing mice show reduced SST levels in the cortex, 101 and this is likely mediated through the interference of amyloid-beta (Ab) with the BDNF-induced activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. 102 In contrast, it appears that inducing increased expression of SST may be beneficial for patients suffering from AD: compounds increasing SST expression are in phase II clinical trials as cognition enhancing agents (FK962, Astellas Pharma, Tokyo, Japan), 103 and transgenic models of amyloid deposition are reversed by environmental enrichment, 25 which is known to induce SST-NPY expression via a BDNF-dependent pathway. Thus, while altered BDNF expression may not represent the primary disturbance in AD, changed expression of, or altered responsiveness to BDNF (and subsequently decreased SST levels) may represent a critical feature of Alzheimer's disease progression.…”

Cognitive status impacts age-related changes in attention to novel and target events in normal adults.

“…Older animals who are more engaged by novel stimuli also tend to exhibit greater preservation of cognitive performance (Rowe, Spreekmeester, Meaney, Quirion, & Rochford, 1998). In a mouse model of Alzheimer's disease, exposure of transgenic mice to an enriched environment has been associated with reduced Aβ levels and amyloid deposition, two components of the neurodegenerative process (Lazarov et al, 2005). In humans, the propensity to allocate attention to novelty is believed to make a major contribution to the cognitive development of children and may play an important role throughout the lifespan (Daffner et al, 1994;Hunt, 1965;Piaget, 1952;Vygotsky, 1968).…”

Strategies for improving cognition with aging: insights from a longitudinal study of antioxidant and behavioral enrichment in canines

“…In rodents, improved behavioral function as a consequence of environmental enrichment or physical exercise may be mediated by increased neurogenesis (van Praag et al 2000(van Praag et al , 2005, increased availability of brain growth factors (Cotman and Neeper 1996;Cotman and Berchtold 2002), and possibly by reductions in brain pathology, such as Aβ accumulation typically seen in patients with AD (Adlard et al 2005;Lazarov et al 2005). We have been characterizing the possible mechanisms underlying the cognitive improving effects of the antioxidant diet and behavioral enrichment in canines and have found some interesting dissociations between the two treatments.…”