Enhanced cognitive activity--over and above social or physical activity--is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity

Abstract

Although social, physical, and cognitive activities have each been suggested to reduce the risk of Alzheimer's disease (AD), epidemiologic studies cannot determine which activity or combination of activities is most important. To address this question, mutant APP transgenic AD mice were reared long-term in one of four housing conditions (impoverished, social, social+physical, or complete enrichment) from 1(1/2) through 9 months of age. Thus, a stepwise layering of social, physical, and enhanced cognitive activity was created. Behavioral evaluation in a full battery of sensorimotor, anxiety, and cognitive tasks was carried out during the final 5 weeks of housing. Only AD mice raised in complete enrichment (i.e., enhanced cognitive activity) showed: (1) protection against cognitive impairment, (2) decreased brain beta-amyloid deposition, and (3) increased hippocampal synaptic immunoreactivity. The protection provided by enhanced cognitive activity spanned multiple cognitive domains (working memory, reference learning, and recognition/identification). Cognitive and neurohistologic benefits of complete enrichment occurred without any changes in blood cytokine or corticosterone levels, suggesting that enrichment-dependent mechanisms do not involve changes in the inflammatory response or stress levels, respectively. These results indicate that the enhanced cognitive activity of complete enrichment is required for cognitive and neurologic benefit to AD mice-physical and/or social activity are insufficient. Thus, our data suggest that humans who emphasize a high lifelong level of cognitive activity (over and above social and physical activities) will attain the maximal environmental protection against AD.

Fig. 1. Impoverished (IMP), social activity (SH), physical activity (PA), and complete environmental enrichment (EE) housing environments

With this design, a step-wise ascension toward the complete EE paradigm was created. Transgenic mice were raised in one of these environments from 1.5 through 8.5 months of age. A group of socially housed non-transgenic mice were included as a standard housed control.

Fig. 2. Morris water maze overall acquisition and probe-trial memory retention

(A) EE mice showed better spatial learning than several other transgenic groups overall. (B and C) No group differences were observed for percent time spent in the former platform-containing quadrant (Q2) or in annulus crossing. * = EE group significantly lower latencies than IMP and PA (p<0.05). Abbreviations: NT, non-transgenic socially-housed mice; IMP, transgenic singly-house (impoverished) mice; SH, transgenic socially-housed mice; PA, transgenic socially-housed mice with physical activity; EE, transgenic “complete” environmentally-enriched mice.

Fig. 3. Recognition/Identification performance in platform recognition testing overall (A) and for each of the 4 days of testing (B)

Over all 4 days of testing (A), all transgenic groups except EE mice were significantly poorer in performance compared to NT controls. Across individual test days (B), NT mice and EE mice rapidly reduced their escape latency, while IMP, SH, and PA mice had a slower reduction in latency. * = significantly higher escape latencies than NT group at p<0.05 or higher levels of significance. Abbreviations: as in Figure 1.

Fig. 4. Radial arm water maze overall and final block escape latencies

(A) In overall working memory performance, NT had significantly lower escape latencies than IMP, PA, and SH mice on both overall trial 4 (T4) and trial 5 (T5). In contrast, EE mice were indistinguishable from the NT group. * = significant difference for NT vs. IMP, SH, and PA at p<0.02 or higher level of significance. (B, C) Final block escape latencies for working memory trials T4 and T5. For T4, NT mice achieved significantly lower escape latencies compared to SH and PA mice, while EE mice were no different from NT controls. * = significantly different from NT group at p<0.02. During T5, both NT and EE groups had significantly lower latencies compared to all other groups (IMP, SH, PA). ** = significantly different from both NT and EE at p<0.025 or higher level of significance. Abbreviations: as in Figure 1.

Fig. 5. Plasma corticosterone levels by housing environment (A), genotype (B), and gender (C)

No housing or transgenic differences were observed in corticosterone levels. In contrast, male mice had almost 3-fold lower levels of corticosterone compared to female mice. * = significantly lower at p<0.01. Abbreviations: Tg+, all transgenic mice combined; M, male; F, female; all other abbreviations as in Figure 1.

Fig. 6. Standardized mean signal intensities for 10 plasma cytokines in APP+PS1 and NT mice

No group differences were observed for any cytokine measured. Abbreviations: as in Figure 1.

Fig. 7. Effects of housing environment on total Aβ deposition in APPsw+PS1 mice

Of the 4 housing environments, only the enhanced cognitive activity provided by “complete” enrichment (EE) was capable of reducing Aβ deposition. Significant reductions in total Aβ deposition were seen in both hippocampus (A) and entorhinal cortex (B) for EE-housed mice. *p<0.25, **p<0.005 versus Tg mice housed in all other environments. (C) Photomicrographic examples of hippocampal Aβ immunostaining from Tg mice raised in impoverished housing (IMP), social housing (SH), physical activity housing (PA), and complete enrichment (EE) housing. Note the reduced Aβ deposition seen only in complete EE-reared mice. Scale bar = 100 μm

Fig. 8. Synaptophysin immunoreactivity in CA1 and CA3 hippocampal areas for APPsw+PS1 mice raised in various housing environments

Transgenic mice raised in “complete” EE (enhanced cognitive activity) had increased synaptophysin immunoreactivity in hippocampal CA1 (A) and CA3 regions (B) compared to transgenic mice raised in all other housing environments. *p<0.05, **p<0.005 vs. all other groups. (C) Photomicrographic examples of synaptophysin immunoreactivity in hippocampal CA1 (left panels) and CA3 (right panels) for transgenic mice raised in IMP, SH, PA, or EE housing. Note the enhanced synaptophysin immunoreactivity seen exclusively for Tg mice raised in complete EE housing (i.e., enhanced cognitive activity). Scale bar = 50 μm.