Alzheimer’s disease (AD) is an insidious, age-dependent progressive neurodegenerative disorder characterized by deficits in cognitive function. The pathological changes of AD are diffuse atrophy of the cerebral cortex, deepening of cortical sulci, and narrowing of cerebral gyri, in which the loss of neurons, the extracellular deposition of amyloid-beta (Aβ) peptide as senile plaques (SPs), and the formation of neurofibrillary tangles (NFTs) are characteristic [1
]. Up to now, a series of studies on the pathogenesis of AD have been conducted, and several hypotheses including Aβ cascade [3
], abnormal tau phosphorylation [4
], increased apolipoprotein E (APOE) [5
], and neuroinflammation [6
] have been widely recognized. However, no hypothesis has been completely elucidated on the complex pathological changes of AD.
Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role [7
]. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age [9
]. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including AD [11
]. Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including Aβ production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death [20
]. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration [22
]. As a result, autophagy has a crucial role in the regulation of longevity.
Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death [23
]. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons [25
]. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, 5′-adenosine monophosphate-activated protein kinase (AMPK), and glycogen synthase kinase 3 (GSK-3) [26
]. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dys-regulated mTOR signaling in AD [28
]. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD [30
]. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, NFTs, and cognitive impairment in clinical presentation [31
]. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.
It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits [34
]. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection [35
]. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues [36
]. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains [37
]. Interestingly, our recent study has also documented that the brain aging of d
-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation [39
]. Therefore, physical activity is regarded as an effective approach against AD. The aim of this article is to overview the potential of physical activity as a preventive or therapeutic strategy for AD through regulating the mTOR signaling pathway. In this article, we summarize the main features of AD pathogenesis, the regulatory roles of mTOR in AD, and the preventive or therapeutic implications of targeting the mTOR signaling pathway with physical activity or exercise intervention.
3. The Alteration of miRNAs in AD and Aging-Related Diseases
MicroRNAs (miRNAs), small non-coding RNAs with a length of 18–25 nucleotides, usually downregulate the expression of mRNA and protein upon targeting specific mRNAs, and are involved in complex post-transcriptional regulatory networks and the maintenance of healthy cellular functions [79
]. Approximately 70% of known miRNAs enriched in the brain are involved in critical roles, including neuronal development and differentiation, synaptic plasticity, and the pathogenesis of neurodegenerative disorders [83
]. The expression of some miRNAs is dynamically regulated during brain development, neurogenesis, and neuronal maturation [84
]. In recent years, growing evidence has demonstrated that abnormal patterns of miRNAs are linked with most aging or aging-related neurodegenerative diseases [83
]. In APP/PS1 mice, miR-99b-5p and miR-100-5p are reported to be decreased and increased at early and late disease stages compared with age-matched wild-type mice, respectively [86
]. In addition, miR-99b-5p and miR-100-5p are reported to affect neuron survival by targeting mTOR, which is consistent with previous studies in cancer [87
]. The defensive effect of miR-200b or miR-200c on Aβ-induced toxicity in AD models are observed, which is evidenced by the relieving of impaired spatial learning and memory induced by intracerebroventricular injection of oligomeric Aβ after the treatment of miR-200b or miR-200c [90
]. Mechanically, the miR-200b/c could suppress the downstream effector of mTOR, S6K1. Chronic cerebral hypoperfusion (CCH) is a high-risk factor for vascular dementia and AD. Similar to a previous study, some miRNAs have also been validated to regulate autophagy-related signal pathways [39
]. It is reported that the level of miR-96 is significantly increased in a CCH rat model established by two-vessel occlusion (2VO), and the inhibition of miR-96 can attenuate the cognitive impairment. Furthermore, miR-96 antagomir injection can attenuate the number of LC3 and Beclin1-positive autophagosomes in 2VO rats. In contrast, the overexpressed miR-96 can downregulate mTOR protein levels in 2VO rats and primary culture cells [91
]. These findings suggest that miR-96 may play a key role in autophagy under CCH by regulating mTOR signaling. Since pathological changes occurring in AD and Parkinson’s diseases (PD) brains are reflected in cerebrospinal fluid (CSF) composition, CSF represents an optimal biomarker source of neurodegenerative diseases. One study [92
] related to CSF miRNAs has reported that 74 miRNAs are downregulated and 74 miRNAs are upregulated in AD patients when compared with controls based on a 1.5-fold change threshold. The study identified a set of genes involved in the regulation of tau and Aβ signal pathways in AD, with mTOR and BACE1 being targeted by the CSF miRNAs. Another study [93
] has demonstrated that miR-153, miR-409-3p, miR-10a-5p, and let-7g-3p are significantly overexpressed in CSF exosomes from PD and AD patients. Bioinformatic analysis has demonstrated that mTOR signaling, ubiquitin-mediated proteolysis, dopaminergic synapses, and glutamatergic synapses are the most prominent pathways, with differential exosomal miRNA patterns associated with the development of PD and AD. These results have demonstrated that CSF miRNA molecules are reliable biomarkers with fair robustness in regard to specificity and sensitivity in differentiating PD and AD patients from healthy controls. Among these processes, the mTOR signaling pathway is an important target.
The roles of miRNAs in APP and Aβ production, synaptic remodeling, neuron survival, and glia cell activation have also been identified [94
]. miRNAs, including miR-130a, miR-20a, miR-29a, miR-106b, miR-128a, miR-125b, and miR-let-7c, have been reported to be downregulated in aged individuals and in different human and animal cell aging models [85
]. In the brain, miR-29 is reported to target BACE1, and the deregulation of miR-29b results in an increase of apoptosis in AD. The overexpression of miR-29 in humans and transgenic mice could decrease endogenous BACE1 levels and increase Aβ production [79
]. MiR-107 also targets BACE1, and can induce cell cycle arrest, because cell cycle re-entry is an early event in AD pathogenesis [98
]. Of course, there are some brain-specific miRNAs that participate in tau hyperphosphorylation, the physiological regulation of APP expression, and the generation and deposit of Aβ. The expression of extracellular signal-regulated kinase 1 (ERK1) is a direct tau kinase. Some miR-15 family members can target ERK1 to be involved in tau hyperphosphorylation [79
]. For example, as a neuron-specific miRNA, the expression of mature miR-124 is reduced in a subset of AD patients [99
]. Downregulation of miR-124 can result in the altered splicing of APP and promote the conversion of APP to Aβ. Similarly, the downregulation of miR-17, miR-101, and miR-16a also promotes accumulation of APP [33
]. Previous studies have documented that the abnormally low expression of miR-16 could potentially lead to the accumulation of APP protein in the embryo of SAMP8 mice and BALb/c mice, suggesting APP as a target of miR-16 [100
]. The miR-101 and miR-106 can also target APP, in turn, resulting in an elevated generation and accumulation of Aβ [101
]. miR-455-3p is found to be significantly upregulated in serum samples, postmortem brains, mouse models, and cell lines of AD [102
]. Recent evidence has shown that circulating miR-455-3p is upregulated in AD postmortem brains when compared with healthy control samples [81
], suggesting that miR-455-3p may be a potential biomarker for AD. The miR-206 regulating brain-derived neurotrophic factor (BDNF) is markedly increased in AD model mice [103
]. Because changes in gene expression and splicing of APP are associated with the generation and deposition of Aβ, specific neuronal miRNAs can regulate APP splicing. Therefore, the scanning and identification of miRNAs in the future could provide an important new insight and elucidation in the initiation and progression of AD. Nevertheless, the roles of far more miRNAs still remain enigmatic in AD etiology.
6. mTOR as a New Target for the Prevention and Treatment of AD During Physical Activity?
As reported above, mTOR seems to be an interesting candidate target for the regulation of AD, and the role of physical activity as a neuroprotective agent is well recognized. Some literature has also reported that mTOR is a regulatory target of AD during physical activity.
mTOR signaling is dynamically regulated by upstream components including PI3K/Akt, AMPK, mitogen-activated protein kinase (MAPK), p53, liver kinase B1 (LKB1), erb-b2 receptor tyrosine kinase 2 (ERBB2), insulin receptor substrate 1 (IRS-1), phosphatase and tensin homolog (PTEN), GSK-3, and insulin/insulin-like growth factor 1 (IGF-1). PI3K/Akt, AMPK, GSK-3, insulin/IGF-1, and AMPK play a critical role in regulating the generation of Aβ and the aberrant phosphorylation of tau [27
]. PI3K-Akt can activate mTOR-mediated biosynthetic processes, whereas it also can also simultaneously repress autophagic degradation. Previous findings have demonstrated that aberrant activation of neuronal PI3K/Akt/mTOR signaling is an early pathogenesis in the brain of AD individuals and a major candidate for pathophysiological change of Aβ. In addition, the abnormal PI3K/Akt/mTOR signaling pathway has been shown to contribute to the development of AD [27
]. Based on the relationship between upstream components of mTOR signaling and autophagy, physical activity should be beneficial to the prevention and alleviation of AD through regulating PI3K/Akt and AMPK signaling.
According to previous reports, the hyperactivation of mTOR can suppress autophagy, which directly contributes to hyperphosphorylation and the aggregation of tau protein [43
]. Thus, the inhibition of mTOR represents one of the major mechanisms benefitting the pathogenesis of AD in the presence of physical activity. Of course, the effect of exercise on mTOR activity depends on the type and intensity of exercise. Jeong et al. [143
] have reported abnormal mTOR phosphorylation and impaired autophagy, such as decreased Beclin1 and LC3B, and increased p62 in the cerebral cortex of NSE/htau23 transgenic mice. Interestingly, 12-week treadmill exercise intervention significantly improves learning and cognitive capacity of NSE/htau23 transgenic mice. Mechanically, abnormal mTOR, impaired autophagy, and the hyperphosphorylation and aggregation (Ser199/202, Ser404, Thr231, PHF-1) of tau protein are improved upon exercise intervention. Meanwhile, Antonella has observed a strong activation of the mTOR signaling pathway, and an increase in two mTOR downstream targets, p70S6K and 4EBP1, in both amnestic mild cognitive impairment (MCI) and AD patients when compared with that of the controls [144
]. Interestingly, p70S6K and 4EBP1 are dramatically increased in AD, and are also positively correlated with tau phosphorylation [145
], thus the activation of p70S6K and 4EBP1 has been identified as a contributor to hyperphosphorylated tau. In contrast, the significant autophagy impairment has also been found. These findings suggest that the alteration of mTOR signaling and autophagy occurs at the early stage of AD. Consistent with previous findings, one study has established a relationship between mTOR signal activation and AD, and a possible correlation of mTOR activation with the degree of cognitive impairment in AD [147
]. Besides regulating autophagy and mTOR, 12-week treadmill exercise from the age of 24 months has been reported to markedly suppress Aβ-dependent neuronal cell death and upregulate the expression of NGF, BDNF, and phosphor-CREB in the hippocampal tissue of Tg mice [148
]. Furthermore, treadmill exercise may specifically repress GSK-3α/β activity via elevated PI3K and Akt phosphorylation in hippocampal tissue. In a 20-week high-fat diet (HFD) rat model, eight-week treadmill exercise significantly decreased tau hyperphosphorylation and aggregation, while increasing insulin signaling-related protein activity [149
]. The above findings suggest that treadmill exercise can provide a therapeutic potential to inhibit tau, Aβ-42, and neuronal-death signal pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.
AMPK, as a key enzyme for energy metabolism, regulates cellular metabolism to maintain energy homeostasis in response to the reduction of intracellular ATP levels. AMPK is activated when cellular ADP level is increased with the accompanying changes in cellular energy status [150
]. AMPK has been implicated in aging and neurodegenerative diseases [151
]. In addition, AMPK also participates in the regulation of Aβ level and limits the generation of Aβ by inducing autophagy [141
]. Increasing data have demonstrated the close relationship between AMPK signaling and major hallmarks of AD [154
]. T2MD is a risk factor for AD, and diabetic populations at the midlife stage carry a 1.5-times higher risk for developing AD than those diagnosed with T2DM at a late stage in life [158
]. Impaired insulin sensing in the brain, diabetes, and metabolic syndrome (MetS) are associated with the pathogenesis of AD, MCI, and other neurological disorders [159
]. One recent study [160
] demonstrated that mixed intervention, such as nutritional ketosis combined with high-intensity interval training (HIIT) (in order to inhibit mTOR signaling) for 10 weeks, can significantly reduce HgA1c, fasting insulin, and insulin resistance, as well as restore memory function, improve neuroplasticity, and normalize MetS biomarkers of patients via activating the AMPK signaling pathway. This finding suggests that mTOR suppression and AMPK induction may functionally halt neurological disease progression and restore early-stage memory loss. In addition, previous studies have reported mTOR as a target of physical activity in triple-negative breast cancer (TNBC), and physical activity at moderate to vigorous intensity induces the inhibition of PI3K-Akt-mTOR signaling and slows the growth of TNBC cells [161
Up to now, the underlying mechanisms of physical activity for mediating these benefits have remained unclear. The neurophysiological effects of physical activity and regular exercise are thought to be mediated by various molecular mechanisms, including the upregulation of BDNF, IGF-1, and related molecules such as Ca2+
/calmodulin-dependent protein kinase II (CaMKII) and calcineurin, which are associated with learning and memory functions and can, in turn, enhance brain plasticity and improve performance of memory tasks. Forced treadmill running for five days can induce an increase of BDNF protein level within the brain tissues of animals by 70%, which is associated with the increased activation of BDNF receptors and subsequent mTORC1 signaling in hippocampal tissue [144
]. Another study has also explored the effect of regular exercise on the upregulation of BDNF, the phosphorylation of BDNF receptors such as tropomyosin-related-kinase (Trk), and the activation of PI3K/Akt [145
]. Reelin is an extracellular, secreted glycoprotein that is essential for neuronal migration, synaptic plasticity, and brain development. During the development of the brain, regular exercise increases the production of reelin [146
]. In addition, regular exercise can shift the redox state of the brain. Previous studies have also confirmed the minimal change of lipid peroxidation in hippocampal tissue after regular exercise training [37
]. Interestingly, BDNF also possesses metabotropic properties besides its neurotrophic effect. BDNF can upregulate expression of AMPK, ubiquitous mitochondrial creatine kinase (uMtCK), and uncoupling protein 2 (UCP2) [164
]. Thus, it is reasonable to suggest that low expression or activity of BDNF can significantly lead to the alteration of these metabolic factors, thus eventually disrupting learning and memory functions. Meanwhile, AMPK, as an activator of autophagy, can slow down the progression of AD [153
]. According to the data that the Aβ level in an AD brain is determined by the overall functional status of autophagy, AMPK activation can facilitate the triggering of autophagy and promote lysosomal degradation of Aβ through suppressing mTOR signaling.
In this review, we have reported that physical activity not only can attenuate cognitive impairment, but also inhibit the generation of Aβ in different AD models. What is more important, physical activity can induce autophagy in AD rats and mice. Furthermore, physical activity can significantly decrease expression of PI3K, p-Akt, and mTOR at the protein level, respectively. Taken together, AMPK/mTOR signaling may improve insufficient energy metabolism and execute the clearance of Aβ and NFTs via the autophagy signal pathway. Physical activity can inhibit Aβ generation and induce autophagy by downregulating the PI3K/Akt/mTOR signaling pathway, and further can reveal a neuroprotective effect. It seems that physical activity might be a candidate as a neuroprotective agent for AD treatment by inducing autophagy.