Treadmill Exercise Facilitates Synaptic Plasticity in APP/PS1 Mice by Regulating Hippocampal AMPAR Activity

Abstract

Accumulating evidence underscores exercise as a straightforward and cost-effective lifestyle intervention capable of mitigating the risk and slowing the emergence and progression of Alzheimer's disease (AD). However, the intricate cellular and molecular mechanisms mediating these exercise-induced benefits in AD remain elusive. The present study delved into the impact of treadmill exercise on memory retrieval performance, hippocampal synaptic plasticity, synaptic morphology, and the expression and activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) in 6-month-old APP/PS1 mice. APP/PS1 mice (4-month-old males) were randomly assigned to either a treadmill exercise group or a sedentary group, with C57BL/6J mice (4-month-old males) as the control group (both exercise and sedentary). The exercise regimen spanned 8 weeks. Our findings revealed that 8-week treadmill exercise reversed memory retrieval impairment in step-down fear conditioning in 6-month-old APP/PS1 mice. Additionally, treadmill exercise enhanced basic synaptic strength, short-term potentiation (STP), and long-term potentiation (LTP) of the hippocampus in these mice. Moreover, treadmill exercise correlated with an augmentation in synapse numbers, refinement of synaptic structures, and heightened expression and activity of AMPARs. Our findings suggest that treadmill exercise improves behavioral performance and facilitates synaptic transmission by increasing structural synaptic plasticity and the activity of AMPARs in the hippocampus of 6-month-old APP/PS1 mice, which is involved in pre- and postsynaptic processes.

Keywords: AMPA receptor; Alzheimer’s disease; exercise; synaptic plasticity.

Figure 1

Experimental design. Mice destined for exercise underwent a 3-day treadmill acclimation period. Over an 8-week period, the exercise groups ran daily for 60 min, 5 days per week. Behavioral performance and molecular changes were assessed after the intervention. AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group.

Figure 2

Treadmill exercise reversed memory retrieval deficits in 6-month-old Tg mice on a step-down inhibitory avoidance task. (A) Compared with CS, the error frequency was significantly higher (p < 0.001); the latency significantly decreased (p < 0.001); (B) and the standard rate was lower (p = 0.038) (C) in 6-month-old Tg mice. Eight weeks of aerobic exercise significantly improved the behavioral performance (error frequency, p < 0.001; latency, p < 0.001) (A), (B) and increased the standard rate (C). AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. *, p < 0.05; ***, p < 0.001.

Figure 3

Treadmill exercise facilitated basal synaptic strength and STP within the hippocampus of 6-month-old Tg mice. (A) Illustrative recordings of fEPSPs at Schaffer collateral-CA1 synapses, showcasing variations across varying stimulus intensities. (B) In comparison to CS, acute hippocampal slice recordings from Tg mice exhibited a marked reduction in AMPA receptor-mediated fEPSPs within the stratum radiatum across all tested stimulation intensities (p < 0.001). An eight-week treadmill exercise regimen significantly bolstered the basal synaptic strength in both 6-month-old Tg (p = 0.025) and Wt mice (p < 0.001). (C) Representative traces of paired-pulse EPSPs at interpulse intervals spanning 20–400 ms, encompassing all four experimental groups. (D) In contrast to CS, PPF measurements at interpulse intervals of 20–400 ms were significantly diminished in 6-month-old Tg mice (20 ms, p < 0.001; 50 ms, p = 0.018; 100 ms, p = 0.006; 200 ms, p = 0.018; 400 ms, p = 0.013). Furthermore, eight weeks of treadmill exercise led to a significant decrease in PPF in both 6-month-old Tg mice across the same intervals (20 ms, p = 0.004; 50 ms, p < 0.001; 100 ms, p = 0.002; 200 ms, p < 0.001; 400 ms, p = 0.047) and Wt mice at 20 ms (p = 0.015). AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Figure 4

Treadmill exercise facilitated LTP in the hippocampus of 6-month-old Tg mice. (A) Representative LTP traces from different groups. (B) A markedly diminished fEPSP slope in Tg mice compared to that in Wt mice (p < 0.001). An eight-week treadmill exercise regimen robustly augmented the fEPSP slope in both Tg (p < 0.001) and Wt mice (p < 0.001). AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. ***, p < 0.001.

Figure 5

Treadmill exercise ameliorated synaptic pathology of the hippocampus in 6-month-old Tg mice. (A) Representative transmission electron microscope photos of different groups. (B) Representative measurement of synaptic structural parameters. When comparing the Tg mice to the CS group, notable deficiencies were observed in synapse number (C), p = 0.001), synaptic interface curvature ((D), p < 0.001), synaptic active zone length ((E), p = 0.003), and thickness of PSD ((F), p = 0.001), accompanied by a widened synaptic cleft ((G), p = 0.005). Remarkably, an eight-week treadmill regimen reversed these trends, significantly boosting synapse count ((C), p < 0.001), synaptic interface curvature ((D), p = 0.002), synaptic active zone number ((E), p < 0.001), and thickness of PSD ((F), p = 0.004) and narrowing the synaptic cleft ((G), p = 0.023) in Tg mice aged 6 months. Scale bar = 0.5 μm. AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. **, p < 0.01; ***, p < 0.001.

Figure 6

Treadmill exercise increased the expression and activity of AMPAR in 6-month-old Tg mice. (A) Representative immunoreactive bands detected by Western blot. In comparison to CS, the expression of GluA1 ((B), p = 0.001), GluA1 S831 ((C), p < 0.001), CaMKIIα ((D), p < 0.001), GluA2 ((E), p = 0.044), GluA1 S845 ((F), p < 0.001), and PKA ((G), p < 0.001) in the hippocampus of Tg mice is significantly diminished. Notably, an eight-week treadmill exercise regimen significantly elevates the expression of these proteins, including GluA1 ((B), p < 0.001), GluA1 S831 ((C), p < 0.001), CaMKIIα ((D), Tg: p < 0.001; Wt: p = 0.009), GluA2 ((E), p < 0.001), GluA1 S845 ((F), Tg: p < 0.001; Wt: p = 0.001), and PKA ((G), Tg: p < 0.001; Wt: p = 0.001) in both Tg and Wt mice. AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. *, p < 0.05; **, p < 0.01; ***, p < 0.001.

Figure 7

Treadmill exercise increased ANR of the hippocampal pyramidal neurons in 6-month-old Tg mice. (A) Representative EPSCs recorded from hippocampal pyramidal neurons in slices prepared from different groups. (B) The decrease in ANR observed in Tg mice was reversed by treadmill exercise (p = 0.048). AS, APP/PS1 sedentary group; AE, APP/PS1 exercise group; CS, C57BL/6J sedentary group; CE, C57BL/6J exercise group. *, p < 0.05.