Physical exercise improves memory and cognition in physiological aging and Alzheimer’s disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aβ oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3β, Aβ oligomers (Aβ dimers and trimers), pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3β kinase activity, decreases in the levels of Aβ oligomers, pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3β kinase activity.

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.

Background/Objectives: Caffeine is widely recognized as an ergogenic aid, yet evidence regarding its acute effects on repeated sprint ability (RSA) remains inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of acute caffeine ingestion on RSA across different populations, exercise modalities, and dosage levels. Methods: A comprehensive literature search was conducted in the PubMed, EBSCO, Cochrane Library, Web of science, and Scopus databases. Data were pooled using the weighted mean difference (WMD) with 95% confidence interval (CI). Results: Thirteen studies met the inclusion criteria. Acute caffeine ingestion significantly enhanced RSA peak power output (PPO) compared with placebo (WMD, 5.28; 95% CI, 2.49 to 8.07; p = 0.0002). Subgroup analyses revealed significant improvements in both males (WMD, 13.11; 95% CI, 5.63 to 20.59; p = 0.0006) and females (WMD, 4.03; 95% CI, 1.10 to 6.97; p = 0.007). A caffeine dose of ≥6 mg/kg body weight (BW) produced greater ergogenic benefits (WMD, 6.67; 95% CI, 3.32 to 10.02; p < 0.0001) than lower doses (WMD, 2.16; 95% CI, −2.87 to 7.19; p = 0.40). Moreover, a more pronounced enhancement was observed in cycling-based RSA (WMD, 8.77; 95% CI, 1.98 to 15.56; p = 0.01) compared with running-based protocols (WMD, 4.56; 95% CI, 1.58 to 7.55; p = 0.003). Conclusions: Acute caffeine ingestion significantly enhances RSA, particularly at doses ≥6 mg/kg BW. This effect is consistent across both male and female participants, with no statistically significant sex difference observed in the pooled analysis. These findings reinforce caffeine’s role as an effective ergogenic aid for optimizing high-intensity intermittent performance, with the strongest benefits evident in cycling exercise.