The effects of treadmill exercise on autophagy in hippocampus of APP/PS1 transgenic mice

Abstract

The β-amyloid (Aβ) deposition is one of the major pathological hallmark of Alzheimer’s disease. Dysfunction in autophagy has been reported to lead to the Aβ deposition. The current study aimed to investigate the effects of treadmill exercise on autophagy activity and the Aβ deposition and to demonstrate whether exercise-induced reduction in the Aβ deposition was associated with changes in autophagy activity. APP/PS1 transgenic mice were divided into transgenic sedentary (TG-SED, n=12) and transgenic exercise (TG-EXE, n=12) groups. Wild-type mice were also divided into sedentary (WT-SED, n=12) and exercise (WT-EXE, n=12) groups. The WT-EXE and TG-EXE mice were subjected to treadmill exercise for 12 weeks. The levels of Aβ plaques and soluble forms of Aβ, autophagy markers light chain 3 and P62, and lysosomal marker lysosome-associated membrane protein 1 (Lamp1) were measured in the hippocampus. Both Aβ plaques and soluble forms of Aβ (Aβ40 and Aβ42) were significantly increased in TG-SED mice compared with WT-SED mice, whereas exercise reduced Aβ deposition in APP/PS1 transgenic mice. Coincidentally, TG-SED mice displayed a decrease in autophagy activity as evidenced by a significant increase in the levels of light chain 3-II and P62, as well as an accumulation of lysosome as evidenced by a significant over-expression of Lamp1. Interestingly, exercise increased autophagy activity as evidenced by a significant reduction in the levels of P62 and Lamp1 in TG-EXE mice. These findings suggest that treadmill exercise is efficient in decreasing Aβ deposition by enhancing autophagy–lysosomal activity in APP/PS1 transgenic mice, demonstrating a possible approach in Alzheimer’s disease prevention and treatment.

Endosomal-lysosomal dysfunction in metabolic diseases and Alzheimer's disease

“…While an increase in LC3II expression typically is thought to be associated with upregulation of autophagy, when it accumulates in concert with increases in SQSTM1/p62, it is indicative of a decrease in degradation of autophagosomal substrates (Yoshii and Mizushima, 2017). Furthermore, Zhao et al (2018) argue that the elevated LAMP1 in APP/PS1 mice suggests an accumulation of lysosomes and reduced clearance of autophagic substrates and is consistent with prior findings in this AD model. In contrast, exercise in APP/PS1 mice led to a further increase in LC3II expression and decreases in both SQSTM1/p62 and LAMP1, which are results consistent with an increase in autophagic flux that likely explains, at least in part, the reduction in Aβ plaque accumulation.…”

“…SQSTM1/p62 is degraded during autophagy, so a decrease in protein levels is generally associated with elevated autophagic flux, while SQSTM1/p62 accumulation is indicative of autophagy impairment. Zhao et al (2018) found that exercise reduced Aβ plaque deposition in the APP/PS1 transgenic model of AD, which has reduced autophagy activity relative to wild-type mice as indicated by the combination of increases in LC3II and SQSTM1/p62, as well as an overabundance of the lysosomal protein LAMP1. While an increase in LC3II expression typically is thought to be associated with upregulation of autophagy, when it accumulates in concert with increases in SQSTM1/p62, it is indicative of a decrease in degradation of autophagosomal substrates (Yoshii and Mizushima, 2017).…”

“…Eight of thirteen randomized controlled trials found that exercise improves cognitive function in people with AD (Du et al, 2018), and high levels of physical activity were associated with slower clinical decline in autosomal dominant frontotemporal dementia (Casaletto et al, 2020). In healthy humans and monkeys, regular treadmill exercise increased systemic levels of cathepsin B and improved learning and memory (Moon et al, 2016), thus further indicating the neuroprotective potential of the autophagy-lysosomal pathway for healthy brain aging (also see Bayod et al, 2011;Chen and Gan, 2019;He et al, 2012;Zhao et al, 2018). Endurance exercise was also found to be protective in a mouse model of MPTP-induced parkinsonism (Jang et al, 2018), similar to Moon et al (2016) as being associated with increased autophagy and cathepsin proteins.…”

A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

“…In addition, expression of other genes linked to AD progression such as β-site APP-cleaving enzyme 1 (BACE1), presenilin 1 (PS1), insulin-degrading enzyme (IDE), tau, and the receptor for advanced glycation end products (RAGE) are reduced as a consequence of exercise [ 22 , 23 ]. This may be due to a decrease in lipid-raft formation [ 23 ], activation of SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1) [ 12 , 24 ], and an increase in autophagy [ 19 , 25 ]. In addition, exercise has been proposed to mitigate mitochondrial dysfunction [ 11 , 26 ], delay disease-related white matter volume loss [ 27 – 30 ], reduce neuroinflammation [ 19 , 21 , 22 , 31 – 34 ] and oxidative stress [ 10 , 19 , 35 ], repress neuronal cell death [ 36 ], and favor adult neurogenesis [ 17 , 37 – 40 ].…”

Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet?

“…For instance, exercise using treadmill showed a significant decline in oxidative stress and Aβ levels in the hippocampus of an AD rodent model [ 396 - 400 ]. Moreover, physical activity also increased autophagy and improved learning and memory in an AD mouse model [ 399 , 400 ]. Additionally, swimming and running wheels were reported to not only decrease Aβ levels but also improve cognition and motor activity in an AD rodent model [ 401 - 403 ].…”