Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Abstract

Abnormalities in autophagy are associated with Alzheimer’s disease (AD)-like lesions. Studies have shown that exercise can significantly improve AD autophagy abnormalities, but the mechanism underlying this phenomenon remains unclear. APN not only has an important regulatory effect on AD autophagy abnormalities, but also is affected by exercise. Therefore, this study aims to reveal the pathway by which exercise regulates abnormal autophagy in AD using the APN–AdipoR1 signaling pathway as an entry point. The results of the study showed that APP/PS1 double transgenic AD model mice (24 weeks) showed decreased AdipoR1 levels in the brain, abnormal autophagy, increased Aβ deposition, and increased cell apoptosis, and dendritic spines and cognitive function were reduced. Twelve weeks of aerobic exercise enhanced lysosomes and alleviated abnormal autophagy by activating the AdipoR1/AMPK/TFEB signaling pathway in the brains of AD mice, thereby alleviating Aβ deposition and its associated AD-like abnormalities. These findings suggest that the AdipoR1 plays an important role in aerobic exercise’s alleviation of abnormal autophagy in AD brain cells and alleviation of AD-like lesions.

Treadmill exercise can regulate the redox balance in the livers of APP/PS1 mice and reduce LPS accumulation in their brains through the gut-liver-kupffer cell axis

“…The WT group was placed on a stationary treadmill with the SE-AD group during the training time of the exercise group [ 20 ]. Our preliminary results showed that the exercise protocol was effective at reducing pathology of the brain in the AD mice [ 50 ].…”

The dual and emerging role of physical exercise‐induced TFEB activation in the protection against Alzheimer's disease

“…However, treadmill running (60 min with 10 cycles of 4 min at 16 m/min and 2 min at 10 m/min, 4 days/week, for 7 months) increased renal and testicular PP2A levels back to normal levels, playing a preventive role in AD by inhibiting tau hyperphosphorylation and other factors (Szegeczki et al, 2020(Szegeczki et al, , 2021. Furthermore, Jian et al (2022) submitted mice to aerobic exercise (45 min/day at 7−26 m/min, 5 days/week for 12 weeks), verifying that Pp2a gene expression increased in brain cells compared to the sedentary group. Therefore, the PP2A pathway is essential for TFEB activation and tau dephosphorylation.…”

“…A pioneering study demonstrated that treadmill exercise training (45 min/day at 7−26 m/min, 5 days/week for 12 weeks) alleviated cognitive impairment and AD‐like lesions in APP/PS1 mice (Jian et al, 2022). These beneficial results were associated with increased AdipoR1 levels in mice brains, which is considered an agonist that promotes TFEB nuclear translocation (Jian et al, 2022).…”

“…A pioneering study demonstrated that treadmill exercise training (45 min/day at 7−26 m/min, 5 days/week for 12 weeks) alleviated cognitive impairment and AD‐like lesions in APP/PS1 mice (Jian et al, 2022). These beneficial results were associated with increased AdipoR1 levels in mice brains, which is considered an agonist that promotes TFEB nuclear translocation (Jian et al, 2022). Consequently, the authors found an increase in TFEB protein content and upregulation of the expression of lysosomal‐function‐related molecules, such as Cathepsin D, LAMP1, Beclin1, and ATPase H+ transporting V1 subunit H (Atp6V1h), which facilitates a reduction in the dendritic spine density and autophagy abnormalities in the brain.…”

“…TFEB critically regulates lysosomal biogenesis and is related to several vital biological processes, such as brain cell survival, repair, immune function, redox state, and primary metabolism (T. T. Song et al, 2021; Zhu et al, 2021). Using an elegant experimental design, Jian et al (2022) showed that aerobic exercise (45 min/day at 7−26 m/min, 5 days/week for 12 weeks) increased lysosomes and mitigated abnormal autophagy by triggering the Adiponectin Receptor 1 (AdipoR1)/AMP‐activated protein kinase (AMPK)/TFEB signaling pathway in the AD mice brains, which consequently alleviated Aβ deposition, neuronal apoptosis, and improved cognitive function. Therefore, physical exercise‐induced TFEB upregulation is a potential protective mechanism for improving cell clearance and thus becomes a vital target for lysosomal storage disorders.…”