Treadmill Exercise Attenuates Aß-Induced Mitochondrial Dysfunction and Enhances Mitophagy Activity in APP/PS1 Transgenic Mice.

Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), which may be related to mitophagy failure. Previous reports suggest that treadmill exercise protects against mitochondrial dysfunction in AD. However, few studies have investigated the relationship between mitophagy and mitochondrial adaptation caused by treadmill exercise in AD. The current study aimed to investigate whether exercise-ameliorated AD is associated with changes in mitophagy activity. Both Wild-type and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 9 for each group). WTE and ADE mice were subjected to treadmill exercise for 12 weeks, followed by evaluating the effect of treadmill exercise on learning and memory ability, Aß plaques, mitochondrial Aß peptide level, synaptic activity and mitochondrial function. Meanwhile, mitophagy-related proteins PINK1, Parkin, LC3II and P62 were measured in the hippocampal mitochondrial fractions. The results indicated that exercise not only restored learning and memory ability, but also reduced Aß plaque area, mitochondrial Aß peptide level, and increased levels of synaptic markers SYN and GAP43, as well as reversed mitochondrial dysfunction (defective mitochondrial ultrastructure, decreased PGC-1α, TFAM and ATP levels) in APP/PS1 transgenic mice. Moreover, exercise increased mitophagy activity as evidenced by a significant decrease in levels of P62 and PINK1 as well as an increase in levels of LC3II and Parkin in ADE mice. These findings suggest that treadmill exercise can enhance mitophagy activity in the hippocampus, which is efficient in ameliorating pathological phenotypes of APP/PS1 transgenic mice.

Effects of treadmill exercise on mitochondrial fusion and fission in the hippocampus of APP/PS1 mice.

Mitochondrial dysfunction is widely recognized as an early event in the pathogenesis of Alzheimer's disease (AD). Defects in mitochondrial fusion and fission have been proposed to lead to learning and memory impairments in AD. The current study aimed to investigate whether exercise-improved learning and memory were associated with improves in mitochondrial function by increased mitochondrial fusion and decreased mitochondrial fission. APP/PS1 transgenic mice were divided into transgenic sedentary (ADC, n = 15) and transgenic exercise (ADE, n = 15) groups. Wild-type mice were also separated into sedentary (WTC, n = 15) and exercise (WTE, n = 15) groups. The WTE and ADE mice were subjected to treadmill exercise for 12 weeks. In this study, learning and memory were significantly decreased in ADC mice compared with those in WTC mice, whereas exercise improved learning and memory in APP/PS1 transgenic mice. Meanwhile, ADC mice displayed defective mitochondrial function as evidenced by a significant increase in swollen mitochondria and vacuoles, loss of mitochondrial cristae, and decreased ATP levels, as well as an imbalance in mitochondrial fusion and fission as evidenced by significantly increased Drp1 and Mff and decreased Mfn1, Mfn2, and Opa1 in the hippocampus. Interestingly, exercise mitigated mitochondrial dysfunction as evidenced by a significant reduction in swollen mitochondria and vacuoles and increased mitochondrial cristae and ATP levels in ADE mice. Coincidentally, exercise promoted the balance of mitochondrial fusion and fission as evidenced by a significantly decreased Drp1 and Mff and increased Mfn1, Mfn2, and Opa1 in the hippocampus. These findings suggest that treadmill exercise efficiently enhances learning and memory in AD by improving mitochondrial dysfunction in APP/PS1 transgenic mice.