Neuroprotective effects of resistance physical exercise on the APP/PS1 mouse model of Alzheimer's disease

Abstract

Introduction: Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to AD. Most studies, however, have been conducted with aerobic exercises, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD. Similar to AD patients, double-transgenic APPswe/PS1dE9 (APP/PS1) mice exhibit Αβ plaques in the cortex and hippocampus, hyperlocomotion, memory deficits, and exacerbated inflammatory response. Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice.

Methods: For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (CTRL), were distributed into three groups: CTRL, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aβ plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay.

Results: APP/PS1 transgenic sedentary mice showed increased hippocampal Aβ plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aβ alterations to the CTRL levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Despite these alterations, no memory impairment was observed in APP/PS1 mice in the novel object recognition test.

Discussion: Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

Keywords: Alzheimer’s disease; amyloid-beta precursor protein; corticosterone; locomotor activity; resistance exercise.

Figure 1

Experimental design. PBS: phosphate-buffered saline; PFA: paraformaldehyde.

Figure 2

Resistance exercise reduced the number Aβ plaques in the hippocampus of APP/PS1 mice. Representative photomicrographs (scale bar = 40 μm) showing Aβ plaques (arrows) in hippocampal sections of mice from CTRL (A), APP/PS1 (B), and APP/PS1 + RE (C) groups. Graph values (mean ± standard error of the mean) represent the number of Aβ plaques labeled with 6-E10 (D). Asterisks indicate significant differences between groups (*p < 0.05; one-way ANOVA followed by the Dunnett’s posttest), n = 5–6 animals/group.

Figure 3

Resistance exercise increased the number and the recruitment of microglial cells around Aβ plaques in the hippocampus of APP/PS1 mice compared to CTRL or APP/PS1 sedentary animals. Representative photomicrographs (scale bar = 50 μm) of immunofluorescence of Aβ plaques (6-E10, green), microglia (Iba-1, red), and double-stained (6-E10, green + Iba-1, red) with nuclear marker (DAPI, blue) shown in hippocampal sections of mice from CTRL (A), APP/PS1 (B), or APP/PS1 + RE (C) groups, as indicated by arrows. Graph values (mean ± standard error of mean) represent the total number of Iba-1 positive cells (D), the number of Iba-1 positive cells around the Aβ plaques (E), and the area of Iba-1 positive cells around the Aβ plaques (F). One-way ANOVA followed by the Dunnett’s post-test, *p < 0.05, n = 4–6 animals/group.

Figure 4

Resistance exercise decreased plasma corticosterone levels in APP/PS1 mice. Values (mean ± standard error of the mean) represent plasma corticosterone concentration (nM). One-way ANOVA followed by the Dunnett’s post-test, *p < 0.05, n = 5–6 animals/group.

Figure 5

Resistance exercise prevented the occurrence of behaviors presented by the transgenic mice such as the increase in total locomotion (A) and the decrease in the percentage of central crossings (B) of APP/PS1 mice in the open field test to CTRL levels. Values (median ± interquartile range) represent the number of total crossings (A) or the percentage of central crossings (B) of mice in the open field test. Kruskal-Wallis’ test followed by the Dunn’s post hoc, *p < 0.05, n = 13–15 animals/group.

Figure 6

Seven-month-old APP/PS1 mice showed no impairment in short-term recognition memory. Values (mean ± standard error of the mean) represent the discrimination index for the novel object recognition test which was calculated by the ratio of the time spent on the new object minus the time spent in the familiar object to the total time spent on both objects. One-way ANOVA, n = 12–15 animals/group.