Voluntary Wheel Running Reduces Amyloid-β42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer's Disease

Abstract

Exercise has been shown to be protective against the risk of dementias, including Alzheimer's disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities.

Keywords: Amyloid; behavior; dementia; exercise; transgenic.

Fig. 1.

Running parameters. An analysis of running parameters suggests that WT and Tg2576 mice ran similarly. A) Longer access to a running wheel resulted in a greater number of rotations performed B) Mice with 3h and 12h of access to a running wheel ran at a greater speed than 1h mice overall. C) Mice with 3h access to a running wheel exhibited a greater density of running compared to 1h and 12h mice overall. ^@p < 0.05 versus 1h (within that GT), ^#p < 0.05 versus 3h (within that GT).

Fig. 2.

Survival curves. The Log-rank (Mantel-Cox) test found no significant difference between survival curves though exercising groups trended toward reduced mortality.

Fig. 3.

Analysis of body weight and food intake over 4 months of exercise conditions. (Left) WT mice in exercise conditions lost more weight than their SED control counterparts. This effect is not seen in Tg2576 mice. (Right) While all WT exercise groups had increased food intake compared to SED controls only 3h Tg2576 mice ate more than their SED counterparts. *p < 0.05 versus sedentary (within that GT).

Fig. 4.

Analysis of rotarod performance as a measure of physical fitness and open field and Y-maze arm entries as measures of exploratory behavior. (Top) Tg2576 mice were impaired on the rotarod compared to WT mice. In WT mice, exercise increased performance in 1h mice. A similar trend can be seen in Tg2576 mice. (Middle) Tg2576 animals traveled shorter distance in the open field with WT and Tg2576 displaying different trends varying by exercise conditions. Within WTs, 12h mice were less active than all other groups, while in Tg2576 mice 3h mice were more active than all other groups. (Bottom) Overall, Tg2576 mice made fewer entries to the Y-maze. ^{^}p < 0.05 GT difference (within that exercise dose), *p < 0.05 versus sedentary (within that GT), ^@p < 0.05 versus 1h (within that GT), ^#p < 0.05 versus 3h (within that GT), ⁺p < 0.05 versus 12h (within that GT).

Fig. 5.

Analysis levels of Aβ species. A) No significant differences were observed between conditions in the levels of Aβ_40S. B) Compared to Tg2576 SED mice, Tg2576 3h mice expressed lower levels of Aβ_42S. C) No significant differences between conditions in the levels of Aβ_40I. D) The difference between Aβ_42I levels of Tg2576 SED mice and Tg2576 3h mice are approaching significance (p = 0.07), while Aβ_42I levels were also significantly reduced in Tg2576 3h versus Tg2576 1h mice. *p < 0.05 versus sedentary (within that GT), ^@p < 0.05 versus 1h (within that GT).

Fig. 6.

Amyloid plaque levels in the hippocampus. (Top) All exercise groups exhibited reduced hippocampal plaque load compared to SED controls (*p < 0.05 for all except 3h p = 0.054). Although the global effect was significant, there were no discernable differences in amyloid plaque size and morphology between the groups in very localized regions (Bottom).

Fig. 7.

Nonlinear regression analysis between levels of running parameters and insoluble Aβ₄₂ shows benefits of intensity measures and not volume. A) a non-significant moderate negative relationship between running volume and amount of insoluble Aβ₄₂ was found (p = 0.07). B) A significant moderate negative correlation between running speed and amount of insoluble Aβ₄₂ (p = 0.038) was found. C) A moderate negative correlation between running density and amount of insoluble Aβ₄₂ was found (approaching significance p = 0.059). D) Nonlinear regression analyses between running parameters and Aβ plaques in the hippocampus show a very weak non-significant positive correlation between running volume and Aβ plaques, a moderate non-significant negative correlation between speed and Aβ plaques (E), and a moderate negative correlation between density and Aβ plaques that approached significance (p = 0.058) (F).

Fig. 8.

Barnes maze as a measure of spatial learning. (Left) Tg2576 mice exhibited longer latency to enter the escape box compared to WT mice. (Right) All WT groups showed a non-zero learning curve on the Barnes maze. Tg2576 SED mice did not exhibit a learning curve with a slope significantly different from 0. All Tg2576 exercising groups also showed a non-zero learning curve (p < 0.05 for all). Within WT mice, only 3h showed a steeper slope compared to WT SED. ^$non-zero learning slope. ^{^}GT difference (within that exercise dose), *p < 0.05 versus sedentary (within that GT).