Benefits of physical exercise on Alzheimer's disease: an epigenetic view
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Abstract
Increasing lines of evidence have indicated the beneficial impacts of exercise on the neurodegeneration and cognitive decline of Alzheimer’s disease (AD). While general mechanisms underlying the positive effects, including the elevated neurotrophins level, improved neurogenesis and neuroplasticity, restored angiogenesis and autophagy, and reduced neuroinflammation, have been well documented, the epigenetic mechanisms of exercise on AD, however, are still inconclusive. Exercise can regulate the expression of those AD-related genes or proteins through various epigenetic modulations, thereafter rescuing AD pathologies and improving cognitive deficits of AD. In this review, we briefly summarized recent research advances in the beneficial impacts of exercise on cognition and AD and discussed the underlying mechanisms from an epigenetic point of view, including DNA methylation, histone modifications, and non-coding RNAs. A deep understanding of how exercise epigenetically promotes cognitive and pathological recoveries in AD is crucial for the future discovery of precise exercise procedures or exercise-like remedies to treat this disease.
Keywords
INTRODUCTION
Exercise, a subset of physical activity, has been recognized as an important approach to maintaining or improving the health of our body including the brain. Increasing lines of evidence have supported the positive impacts of exercise on emotional and cognitive performance during brain aging, whereas physical inactivity has been considered a risk factor for the incidence and progression of various psychiatric disorders[1,2] and neurodegenerative diseases[3,4]. The neuroprotective effects and general benefits yielded from physical exercise might be due to improved neurogenesis and neuroplasticity, recovered angiogenesis and autophagy, increased neurotrophin secretion, and reduced neuroinflammation[5]. Moreover, recent studies indicate that the positive impacts of exercise on brain function may be achieved through not only those above-mentioned mechanisms but also an epigenetic approach. The roles of epigenetics have gained more and more attention considering its modulating activity to alter chromatin and gene transcription so as to influence brain function. While the benefits of exercise to improve cognition and combat neurodegeneration, including Alzheimer’s disease (AD), have been comprehensively summarized and discussed in previously published reviews[6-10], very limited literature has focused on the epigenetic mechanisms underlying the effects of exercise against AD-related phenotypes and pathologies. In this review, we briefly summarized research advances in the benefits of exercise on brain health and cognition and discussed potential mechanisms underlying the benefits of exercise on AD from an epigenetic point of view.
EPIGENETIC ALTERATIONS IN ALZHEIMER’S DISEASE
Epigenetics
The term epigenetics is derived from the Greek word and mean over or above the genome. In biology, epigenetics was coined in 1942 by Conrad H. Waddington to define the process of how environmental factors regulate gene expression without changing DNA sequence. Epigenetic modifications are essential for many biological processes, especially during early life development and specialization, and may be maintained through cell divisions or inherited through generations. On the contrary, improper epigenetic modulations can result in pathological consequences and are involved in many human diseases. Epigenetic processes are thought to influence gene expression chiefly at the transcriptional and post-transcriptional levels. The common epigenetic modifications include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) regulation. DNA methylation normally associates with gene silencing when the methylation occurs in cytosine-phosphate-guanine (CpG) islands of promoter sequences. Histone modifications lead to the open euchromatin state, which facilitates gene expression, or the closed heterochromatin state, which suppresses gene transcription. In addition, ncRNAs have also been shown to play a key role in the regulation of gene expression.
DNA methylation
DNA methylation is a major epigenetic modification consisting of the covalent addition of a methyl group, transferred from S-adenosylmethionine to cytosine residue within CpG and non-CpG dinucleotide sites, leading to the formation of 5-methyl cytosine (5mC). DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs)[11], resulting in methylation of the DNA and the subsequent alterations of gene expression[12]. There are five members in the family of DNMTs, including DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L[13]. While DNMT1, DNMT3A and DNMT3B are canonical members of DNMTs catalyzing the addition of methylation groups to genomic DNA bases, DNMT2 and DNMT3L are non-canonical family members with relatively low catalytic DNMT activity[13]. However, DNMT3L binds to DNMT3A or DNMT3B to form heterodimers which promote the catalytic activity of DNMT3A and DNMT3B[13].
Oppositely, the level of DNA methylation can be downregulated by DNMTs inhibitors or active removal of 5mC. Ten-eleven translocation (TET) proteins catalyze the conversion of 5mC into
Histone modifications
Chromatin structure and gene accessibility to transcriptional machinery is regulated by modifications to histone tails. The N-terminal tails of histone protein in nucleosomes can be epigenetically modified through phosphorylation, ubiquitination, sumoylation, acetylation and methylation. All these epigenetic modifications modulate the chromatin structure and function to control the transcription and translation of specific genes.
Among all types of histone modifications, the histone acetylation at the ε-amino group of lysine residues in H3 and H4 tails is most consistently associated with the promotion of transcription, whereas the deacetylation of histones correlates with CpG methylation and chromatin inactivation. Compared to acetylation, the impact of histone methylation on transcription is much more complicated. The methylation in the histone N-terminal tail can either promote or repress specific gene expression, depending on the amino acid residue being modified and also on the type of modifications (monomethylated, dimethylated, or trimethylated). For example, the methylation of histone H3 at different amino acid residues leads to contradictory regulation. The methylations on lysine 4 and lysine 36 are associated with transcriptional activation, whereas those on lysine 9 and lysine 27 are associated with transcriptional repression[18].
ncRNAs regulation
ncRNAs are RNA molecules that are transcribed from genomic DNA but do not encode proteins. ncRNAs play essential roles in the epigenetics regulation of gene expression in addition to their roles at the transcriptional and post-transcriptional levels. Interestingly, ncRNAs are particularly abundant in the central nervous system and the altered ncRNAs profile has been closely correlated with brain aging and neurodegeneration[19,20]. ncRNAs can be categorized into small ncRNAs (sncRNA, < 200 nucleotides) and long ncRNAs (lncRNA, > 200 nucleotides). sncRNAs, including microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), modify chromatin structure and silence transcription by guiding Argonaute-containing complexes to complementary nascent RNA scaffolds and then mediating the recruitment of histone methyltransferases and DNMTs. In contrast, lncRNAs control chromatin structure mainly via interacting with nucleosome remodeling factors as well as chromatin-modifying enzymes.
Epigenetic modifications in cognition
In the brain, increasing lines of evidence, either from animal models or human subjects, have implied the involvement of epigenetic modifications in the biological processing of cognition, especially memory formation and consolidation.
DNA methylation and cognition
While the involvement of DNA modifications in memory storage was first proposed in 1969, early studies have further revealed changes in DNA methylation of genes in the hippocampus during learning and memory. Specifically, DNMTs expression is upregulated in the hippocampus following contextual fear conditioning and DNMT is required for the consolidation and reconsolidation of memory-associated neural plasticity[21,22]. Moreover, inhibiting DNMTs expression disrupts contextual fear memory formation, blocks memory maintenance, or improves short-term object pattern separation memory, via modifying the methylation of specific memory-related genes including the brain-derived neurotrophic factor (BDNF), Protein phosphatase 1 and Reelin[23-27].
Notably, while experimental evidence has confirmed the close relationship between DNA methylation or its catalytic enzymes with cognition, the global level of DNA methylation is failed to be correlated with cognitive performance in either healthy older adults or 4 years old children[28-29]. This conflict may highlight a possible involvement of other factors in epigenetic modulations of cognition, especially under pathological conditions such as brain aging and neurodegeneration.
Histone modifications and cognition
Besides DNA methylation, increasing lines of evidence have also revealed important roles of histone modifications such as methylation, acetylation, ubiquitination, or phosphorylation in neuronal plasticity and memory processing[30-33].
Previous studies investigated the contribution of histone methylation to memory formation. Gupta et al found that trimethylation of histone H3 at lysine 4 (H3K4me3), an active mark for transcription, and dimethylation of histone H3 at lysine 9 (H3K9), a silencing mark for transcription, was upregulated in the hippocampus of rats subjected to contextual fear conditioning. In addition, mice deficient in the H3K4-specific histone methyltransferase displayed impaired contextual fear conditioning, suggesting the involvement of histone methylation in long-term memory consolidation[34], which was further supported by other studies[35-37]. Despite the hippocampus, H3K9-mediated transcriptional repression has been found to be required for fear-related memory in other brain regions, such as the entorhinal cortex and amygdala[38,39].
Histone acetylation is also associated with memory and cognition[40,41]. H3 acetylation is rapid and reversible, being controlled by histone acetyltransferases (HATs) and deacetylases (HDACs). HATs activity deficiency leads to impaired learning and memory performance in mice[42,43]. In contrast to HATs, HDACs seem to regulate cognition in an inconsistent way. For Class I HDACs, HDAC1 normally plays a role in memory extinction, whereas HDAC2 and HDAC3 negatively regulate learning and memory[44]. As for the class II HDACs, HDAC4 deficiency was found to be correlated to improved memory in C. elegans[45], while HDAC4 deletion induced memory impairment in mice [46-47]. Moreover, the lack of HDAC5 in mice disrupts the memory process at 10 months of age but not 2 months[48].
Histone phosphorylation is another epigenetic modification regulating cognitive function. Gräff et al. found a rapid H3S10 phosphorylation of histone after the object memory test[49], which was consistent with previous reports showing an increased histone phosphorylation shortly after fear conditioning[50]. Moreover, germline knockout of mitogen-and stress-activated protein kinase 1 (MSK1), a key modulator of histone phosphorylation, impairs long-term spatial and contextual fear memory formation, leaving cued fear memory intact[51]. In addition to MSK1, IκB kinase-α also regulates histone phosphorylation[52] and appears to be involved in the reconsolidation of conditioned fear memories[53].
Moreover, although rarely investigated, recent evidence also suggests a potential contribution of histone ubiquitination in memory formation. Previous studies indicated that the contextual fear conditioning paradigm increased global and gene-specific histone H2B lysine 120 mono-ubiquitination (H2BubiK120) levels in rat hippocampus. Loss of H2BubiK120 impaired LTP and memory formation, which could not be rescued by upregulation of H3K4me3[54].
Notably, various epigenetic modifications involved in cognition usually co-exist with each other rather than work independently. For example, the acetylation of H3K14 works together with the phosphorylation of serine 10 and the trimethylation of H3K36, and H3 acetylation co-occurs with DNA methylation, working together to regulate the memory procecss[32,47,55-58]. It may be worth investigating how a cross-talk or up/down-stream regulation network functions among these co-occurring epigenetic modifications, thereafter, to deepen our current knowledge in the epigenetic regulation of cognition.
ncRNAs regulation in cognition
ncRNAs and their associated functional networks have been implicated in regulating complicated neurobiological processes including cognition and behavior[59-61]. An extensive body of evidence has demonstrated the clear correlations between miRNAs and neuronal activity. Neuronal activity regulates the expression and turnover of neural miRNAs, which in turn permits local translation of mRNAs encoding synaptic proteins at dendritic spines and postsynaptic densities necessary for synaptic function. For example, a specific group of miRNAs, including miR-132, is increased in response to neuronal activity and may ultimately promote the CREB/BDNF signaling-mediated elevation of dendritic spine formation and maturation[62]. However, in another study, miR-132 overexpression decreases MeCP2 expression and impairs cognitive performance in mice. In addition, the brain-specific miR-134 depressed CREB and BDNF expression, thereby impairing synaptic plasticity and recognition performance[63]. Moreover, miR-138-5p, another brain-enriched miRNA, can serve as an important regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus[64]. piRNA, another subtype of sncRNA, induces endured epigenetic changes, which can be inherited across many generations and underlie mechanisms of activity-dependent, adaptive memory storage[65]. For example, aca-piR-F in Aplysia increases piwi/piRNA-dependent methylation at the CREB2 promoter and suppresses CREB2 expression, leading to enhanced long-term synaptic facilitation[66]. Another study found that selective deficiency of PIWI proteins in mice hippocampus results in enhanced contextual fear memory, further supporting the involvement of piRNAs in the regulation of memory[67].
In contrast to those above-mentioned sncRNAs, lncRNA profiles also appear to be correlated with cognition. Intriguingly, although lncRNAs can be found throughout the body, an estimated 40% expresses specifically in the brain, suggesting brain-specific roles for lncRNAs[68]. With advances in high throughput sequencing technologies and functional profiling methods, lncRNAs have been functionally and mechanistically correlated with neurobiological processes responsible for cognition. Previous studies have shown that nuclear lncRNAs may play important roles in the regulation of genes in charge of regulating synaptic plasticity and memory. For example, RNAseq analysis demonstrated an activity-dependent regulation of the lncRNA Gomafu in the medial prefrontal cortex (mPFC) after cued fear conditioning. Knockdown of Gomafu in the mPFC impaired the acquisition of fear responses in cued fear conditioning[69]. Wen et al. found that the down-regulation of lncRNA ANRIL in hippocampal pyramidal neurons ameliorated learning and memory deficits in diabetic rats via the NF-kB signaling pathway[70]. In contrast, NEAT1, a highly abundant nuclear architectural lncRNA, mediates neuronal histone methylation and age-associated memory impairment[71]. In addition to nuclear lncRNAs, cytoplasmic lncRNAs have also been implicated to be involved in synaptic plasticity changes in memory. For instance, lncRNA Durga has been demonstrated to be an important regulator for modulating dendritic morphology and kalirin expression in zebrafish[72].
All these findings provide compelling evidence to support the pivotal roles of ncRNAs in cognition. Further studies are still required to elucidate the consequences of precise spatio-temporal depletion or overexpression of candidate ncRNAs. The yielded data will not only help expand our current knowledge about the exact epigenetic modulating network in cognition but also shed insight into future therapy of diseases with impaired cognition, such as AD.
Epigenetic alterations in Alzheimer’s disease
Impressive achievements have been made in understanding the possible mechanisms for AD pathogenesis and progression. It is well-accepted that AD is a multifaceted disease mediated by interactions between genetic and environmental factors. Currently, most of our knowledge about AD is based on fundamental research works using transgenic animal models carrying artificial genetic backgrounds, which only partially reflect the genetic aspect of this complicated disease. This limitation facilitates our investigations to detect other possible mechanisms to fully understand AD.
Although genetic factors appear to play pivotal roles in the etiology and pathogenesis of early-onset AD[73], epigenetic modifications have gained more attention, especially for late-onset AD[74-77]. More than 20 epigenetic mechanisms have been identified to be correlated to AD, most of which involve DNA methylation, histone modifications [partially summarized in Table 1], or modifications of mRNA-related processes, including ncRNA and miRNA. Various aversive environmental AD risk factors can induce epigenetic modifications of key genes and pathways related to AD and contribute to AD onset. Several factors that have been associated with AD, such as diabetes mellitus, high blood pressure, obesity, diet, excessive sedentary lifestyle, smoking, and even a low educational level, are capable of inducing epigenetic changes. In contrast, a good lifestyle including proper physical exercise, sufficient sleep, vigorous emotional status, proper diet or nutrient supplement and social interactions is currently considered to prevent the pathogenesis of disease, delay the progression, or reduce the severity of AD. Among these daily life factors, physical exercise has been reported as one of the most accessible and feasible approaches.
Epigenetic alterations in the brain of Alzheimer’s disease
| Epigenetic alterations | Target genes (proteins) | Animal models or human subjects | References |
| DNA methylation | HOXA3 and ANK1 | Postmortem human brain tissue in AD patients | [78] |
| IL6 and SIAH1 | Postmortem human brain tissue and blood samples in AD patients. | [79] | |
| ADAM10 | Whole blood DNA from AD patients | [80] | |
| APP | Human brain tissues of AD patients | [81,82] | |
| BACE1 | Prefrontal cortex neurons of AD patients | [83] | |
| ApoE4 and PIN1 | Human brain tissues of AD patients | [84,85] | |
| GSK3β and PP2A | TgCRND8 mice | [86] | |
| ANK1 and WNT5B | Entorhinal cortex of the brain from AD patients | [87] | |
| RIN3, CTSG, SPEG and UBE2L3 | Peripheral blood samples from patients with MCI | [88] | |
| BRCA1 and AURKC | Postmortem brains of AD patients | [89] | |
| ANK1 | Postmortem brains of AD patients | [90,91] | |
| HOXA3, GSTP1, CXXC1-3 and BIN1 | Post-mortem PFC of AD patients (LOAD) | [92] | |
| TNF-α | Cortex samples from 4 healthy subjects and 4 AD | [93] | |
| HOXA | brain tissues from AD patients | [94] | |
| PSD95 | APP/PS1 mice | [95] | |
| PM20D1 | APP/PS1 mice | [96] | |
| Histone acetylation | BACE1, | 3xTg-AD mice brain and PBMC from AD patients | [97] |
| BACE1 and PS1 | APP overexpressed N2a cells | [98] | |
| PS1 and PS2 | Swiss albino mice | [99] | |
| APP | entorhinal cortex samples from AD cases | [100] | |
| DNA methylation and histone acetylation | BIN1 | Human cortical brain tissue | [101] |
| Txnip | 3xTg-AD mice | [102] |
DNA methylation in Alzheimer’s disease
Although the global DNA methylation pattern is failed to be correlated with cognitive performance in healthy human subjects, an altered DNA methylation has been observed in AD brain[103]. Moreover, DNA methylation alterations have also been identified in candidate genes that were closely correlated with AD pathophysiology. For example, in AD, the expression of PSEN1, BACE1 and APP genes, all involved in Aβ production and AD pathology, are promoted by hypomethylation of these gene promoters[75,104]. In addition, hyper-methylation has been associated with a higher presence of the APOE ε4 allele, the strongest genetic risk factor for late-onset AD[105]. As for the neurofibrillary tangles formed by aggregates of hyperphosphorylated tau protein, another pathological hallmark of AD, methylations-mediated epigenetic modulations have also been observed. Hypomethylation of glycogen synthase kinase 3β (GSK3β) promoter results in the overexpression of GSK3β, leading to tau hyperphosphorylation. In contrast, the hypomethylation of protein phosphatase 2A (PP2A) results in reduced activity of PP2A, thus cannot properly dephosphorylate tau, leading to tau hyperphosphorylation[86].
Besides those above-mentioned well-accepted AD risk genes, De Jager et al. also found a close correlation between AD pathology and DNA methylation, especially in the regions of ATP-binding cassette A7 and bridging integrator 1 genes, both of which harbor AD susceptibility alleles[106]. Interestingly, the methylation changes appeared in the early stage of the disease, as evidenced by the fact that these changes appeared in patients with characteristic amyloid pathology, even if they had not yet developed cognitive impairment. In another study, researchers performed a cross-tissue analysis of methylomic profile using AD brain and blood samples from different regions in four independent cohorts. They identified a differentially methylated region in the ankyrin 1 gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation[107].
The DNA methylation status in the hippocampus is further determined, considering its pivotal role in cognition. Chouliaras et al. found that, compared with controls, AD patients showed a reduced 5mC level in hippocampus, which was negatively correlated to both amyloid plaque and tangle in the hippocampus[108]. More specifically, the decreased 5mC was found in both neuronal and glial cells in the CA1 region of hippocampus, whereas only glial cells in the CA3. Moreover, global DNA hypomethylation has been reported to be accompanied by decreased DNMT1 and DNMT3A expression in the hippocampus of postmortem AD samples[109].
DNA methylation alterations have also been observed in the frontal cortex of AD brain, but the findings are somehow inconsistent. For instance, DNA hypomethylation of CpG sites in exon promoter region was observed in the superior frontal gyrus of prefrontal cortex in AD[110]. In contrast, DNA methylation levels were increased in the medial frontal gyrus and were positively correlated with AD pathology[111]. The complexity of the DNA methylation changes in the AD brain was investigated by genome-wide methylation analysis[112]. The results revealed bidirectional DNA methylation alterations in a gene-specific manner; that is, hypermethylated genes were largely related to the regulation of transcription and gene expression, while genes with hypomethylation levels of CpG sites in promoter region were largely related to protein metabolism and membrane transport[112].
Considering the multifaceted nature of AD pathogenesis under complex interplays between environmental and genetic factors, this disease is regulated by a complicated and precisely controlled spatiotemporal gene expression network, which is in turn affected by epigenetic mechanisms including DNA methylation. Although the migration of AD pathologies is temporally and regionally specific according to Brrak staging, it is worth investigating the spatio-temporal profiles of these epigenetic changes, in order to clarify the exact epigenetic modulating network in AD. To reach this goal, multi-omics studies involving spatial omics are a promising direction in the future[113,114].
Histone modifications in Alzheimer’s disease
Histone modifications are also important regulatory pathways in the development and progression of AD. Previous studies have revealed a close relationship between AD and histone acetylation. For example, acetylation of H4 was decreased in APP/PS1 mouse hippocampus. Administration of the HDAC inhibitors rescued the deficit in H4 acetylation and improved cognitive function in AD animal models[115,116]. In addition, HDAC6 inhibitor also blocked the Aβ-induced impairment of mitochondria transport in hippocampal neurons[117], inhibited HDAC6-dependent tubulin deacetylation in the mouse hippocampus, restored impaired axonal transport and novel object recognition in the P301S tau transgenic mouse, and decreased RIPA-insoluble tau accumulation[118]. However, similar to DNA methylation, bidirectional changes in histone acetylation in AD can also be observed. For example, while studies found increased activity of HDAC2 in the brains of patients with AD[119], another study observed downregulated histone marks in quantitative states of H3K18/K23 acetylation[120].
Histone methylation is another best-studied histone modification. In contrast to histone acetylation, although histone methylation has been implicated with cognition[32], the roles of histone methylation in AD are still rarely investigated. One clinical study identified methylation of H2B K108 and H4R55 in the frontal cortex of AD patients[121]. In addition, a postmortem study of AD brain reported an elevated level of H3K9me2 protein in the occipital cortex compared to non-demented and age-matched controls[122]. Much more recently, Persico et al. found a lower H3K4me3 and higher H3K27me3 level in the entorhinal cortex of patients with AD, compared with age-matched control subjects[123]. Consistent with these clinical findings, histone modifications have also been identified in AD animal models. For instance, significant elevation of H3K9me2 and Emt1 (G9a) and Emt2 (GLP) in the prefrontal cortex and hippocampus from the aged AD mouse model are accompanied by reduced glutamate receptor transcription and AD-like cognitive deficits[124]. Moreover, a loss of nuclear H3K4me3 in the hippocampus was found in the 3xTg AD mouse model, while an increase in H3K4me3 and Kmt2a was found in P301S transgenic Tau mice (line PS19)[125]. These epigenetic findings from either clinical or animal studies provide robust experimental evidence to support the involvement of histone methylation in AD. Restoring the homeostasis of histone methylation may be a potential therapeutic strategy to treat AD.
ncRNAs alterations in Alzheimer’s disease
ncRNAs are essential for the proper maintenance of cognitive function and have been represented as important epigenetic mechanisms associated with AD pathogenesis[126-128]. Their expression occurs in a variety of genomic regions important for APP processing, Aβ production, tau pathology, and neurodegeneration. Their regulatory functions are thought to depend on brain development and cell differentiation, as well as on various environmental factors related to AD[129-131].
miRNAs are endogenous sncRNAs regulating gene expression by inhibiting the transcription or inducing degradation of mRNA. Impairment of miRNA-epigenetic regulatory pathway can disrupt chromatin function and consequently lead to neurodegeneration[132-134]. For example, miR-221, miR-144 and miR-374 levels were decreased in the brains of AD patients compared to healthy controls, and the circulating miR-137, miR-181c, miR-9 and miR-29a/b levels in AD were lower than control subjects[135-137]. Jain et al. also found a high expression of miR-27a-3p, miR-30a-5p and miR-34c in the cerebral spinal fluid of AD[138].
As for the regulating mechanisms, meta-analysis indicated that miR-129 is able to regulate synaptic plasticity and is present at low levels in brain regions of AD patients[139-140]. In addition, miRNAs also exert a wide range of modulation on APP processing and subsequent Aβ production. For example, miR-346 specifically targets the APP mRNA 5’-UTR to promote APP translation and Aβ production[141]. On the contrary, miR-455-3p regulates APP processing and protects against mutant APP-induced mitochondrial dysfunction and synaptic abnormalities in AD[142]. Moreover, miR-425, a neuronal-specific regulator is decreased in AD brain and promotes the amyloidogenic processing of APP, neuroinflammation, neuron loss, and cognitive impairment. In contrast, miR-425 supplementation ameliorated amyloid plaque-associated pathological changes and memory deficits[143].
Similar to miRNAs, piRNAs can also exhibit a different expression pattern in AD brain. For example, Qiu et al. identified 103 nominally differentially expressed piRNA from a total of 9,453 piRNAs in brains of AD patients compared with those of control subjects. The expression quantitative trait locus analysis further indicated that most of the 103 AD-related piRNAs were correlated with the genome-wide significant risk SNPs[144]. In another study, Jain et al. identified three piRNAs in the cerebral spinal fluid of AD patients, with a decreased expression level of piR-019324 but increased expression levels of piR-019949 and piR-020364. Interestingly, these piRNA alterations could predict conversion from MCI to AD with an AUC of 0.86. Moreover, the combined analysis of the piRNA profile with phosphorylated tau and Aβ42/40 ratio measurement was able to predict conversion from MCI to AD with a much higher AUC of 0.96[138].
Notably, epigenetic inheritance concerns the mechanisms that ensure the transmission of epigenetic marks from mother to daughter cells. Chromatin modifications and nuclear organization are candidates for epigenetic marks-whether they fulfill the criterion of heritability and what mechanisms ensure their propagation is an area of intensive research. The passage of the replication fork challenges genetic and epigenetic information. Depending on the nature of the epigenetic mark, its inheritance can be ensured in a replication-coupled manner or promptly that is separated from the disruptive event.
IMPACTS OF EXERCISE ON ALZHEIMER’S DISEASE
Cognitive decline induced by brain aging or various pathological conditions can be ameliorated by environmental enrichment (EE) exposure, a complex combination of multiple social, cognitive and physical stimulations[145,146]. EE improves behavior, cognition, and brain function in young senescence-accelerated-prone mice[147]. EE also restores age-related cognitive impairment in mice through transcriptomic mechanisms[148]. Chronic EE exposure relieves cognitive decline and synaptic function induced by prenatal inflammation in aged CD-1 mice[149]. More specifically for AD, EE exposure counteracts Alzheimer's neurovascular dysfunction in TgCRND8 mice[150]. Moreover, EE also prevents synaptic dysfunction induced by Aβ oligomer through miRNA-132 and hdac3 signaling pathways[151]. In humans, clinical trials indicated that enriched gardens improve the cognition and independence of nursing home residents with dementia[152]. Among all factors involved in EE, physical exercise may be the most interesting one and plays an important role in restoring impaired cognition and ameliorating the pathological progression of AD. In this section, we focus on physical exercise to discuss the beneficial impacts of exercise on cognition and AD pathologies.
Beneficial impacts of exercise on brain health and cognition
The benefits of physical exercise on brain health and cognitive function have also been separately investigated in both rodent and human subjects. The benefits might base on various mechanisms on anatomic, cellular and molecular levels. For example, voluntary wheel running reduced the anxiety level of mice, which was associated with changes in the brain fatty acid profile[153]. Treadmill training rescues anxiety and cognitive decline induced by chronic sleep deprivation in mice[154]. Choi et al. found that exercise provided cognitive benefits to 5 × FAD mouse model of AD by the induction of adult hippocampal neurogenesis and BDNF level[155]. Interestingly, administration of plasma from exercised mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice[156]. In human subjects, 12 weeks of simultaneous exercise and cognitive training in visual reality elicit positive changes in brain volume, vascular resistance, memory, and executive function in cognitively normal older adults[157]. In addition, one clinical trial found that vigorous aerobic exercise training may improve specific aspects of cognitive function in individuals with traumatic brain injury[158].
Benefits of exercise on AD pathologies
Studies in humans and animal models suggest that exercise has protective effects against AD, but the underlying mechanisms still require further investigation. Previous studies have found that exercise can stimulate neurogenesis and ameliorate cognitive deficits in AD mouse models through FNDC5/irisin/BDNF signaling[155,159-162]. More interestingly, this pathway has also been involved in neuroprotection by regulating neuroinflammation, improving brain metabolism, and modulating APP processing[163-168], which may also contribute to the benefits of exercise on AD to rescue AD pathologies.
Previous studies have also documented other molecular signaling pathways through which exercise specifically rescues or prevents amyloid or tau pathologies in AD[169-173]. Glycogen synthase kinase-3 (GSK-3) has been confirmed as a key regulator of tau hyperphosphorylation and APP processing, promoting the progression of tauopathy and pathological Aβ aggregation in AD. One previous study found that 5 months of treadmill exercise inhibited GSK-3-dependent signaling, leading to decreased PS1 expression and APP phosphorylation, thereafter dramatically reduced Aβ production and tau phosphorylation in APP/PS1 mice[174]. In other studies, exercise activated PI3K/AKT, the upstream signaling of GSK-3, and inhibited GSK-3, thus mitigating the pathological changes of AD[175,176].
Recently, peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1-α), a transcription coactivator and the upstream signaling molecule of the FNDC5/irisin/BDNF pathway, has been reported to be activated by regular physical exercise and involved in the exercise-rescued cognitive deficits in AD[161]. Exercise epigenetically regulates PGC1α level through modulating methylation of the-260 nt in the PGC1α promoter. PGC-1α is closely associated with mitochondrial function and metabolism and is involved in various diseases including obesity, diabetes mellitus, cardiovascular disease, and neurological disorders. PGC-1α regulates the expression of mitochondrial antioxidant genes, and prevents oxidative stress and mitochondrial dysfunction. Abnormal PGC-1α function disrupts redox homeostasis and exacerbates inflammation, which results in neurodegeneration. During inflammation, the declined PGC-1α level leads to decreased mitochondrial antioxidant gene expression, induces oxidative stress, and promotes NF-κB activation. PGC-1α acts as an essential node connecting metabolic regulation, redox control, inflammation, and neuroprotection[177,178]. Interestingly, the benefits of PGC1-α stimulation on AD pathology can be attributed to its modulating activity on APP processing, especially β-site amyloid precursor protein cleaving enzyme-1 (BACE1), thus resulting in a decreased Aβ production and thereafter reduced pathological Aβ aggregation[179,180].
Notably, PGC1-α is also the substrate of Sirtuin-1 (SIRT1), an important protein controlling histone acetylation. Activation of SIRT1 signaling pathway, induced either pharmacologically (such as osmotin and resveratrol) or non-pharmacologically (photobiomodulation therapy), can rescue neurodegeneration via upregulating a disintegrin and metalloproteinase 10 (ADAM10) and down-regulating BACE1 activity[181-183]. Interestingly, exercise has been reported to recover the downregulated SIRT1 in 3xTg AD mice[184]. Moreover, Koo et al. showed that treadmill exercise promoted SIRT1 expression level, which subsequently caused the activation of ADAM10 by increasing the retinoic acid receptor-β and inhibiting Rho-associated kinase 1[185].
EPIGENETIC MECHANISMS FOR EXERCISE AGAINST ALZHEIMER’S PATHOLOGY
As mentioned above, increasing lines of evidence have indicated that exercise has positive impacts on brain health and cognitive function. However, the exact epigenetic mechanisms responsible are largely unknown. In this context, more and more studies have examined the epigenetic impacts of exercise on brain function under either physiological or pathological conditions [partially summarized in Table 2]. Although the experimental data that link exercise and epigenetics modulation in AD are still limited, these findings may open new avenues helping discover new targets and design innovative therapeutic strategies against AD. In this section, we mainly discussed the epigenetic mechanisms of exercise on AD.
Exercise-related epigenetic changes in the brain
| Exercise | Animals | Brain region | Epigenetic changes | Reference |
| Running wheel | Rats | Dentate gyrus | ↑ histone H3 phospho-acetylation | [189] |
| Treadmill exercise | Rats | Hippocampus | ↓ HDAC activity; ↑ HAT activity; ↑ HAT/HDAC balance | [190] |
| Running wheel | Rats | Hippocampus | ↓ DNA demethylation at Bdnf promoter IV; ↑ pMeCP2 levels; ↑ histone H3 acetylation; ↓ HDAC5 expression | [186] |
| Treadmill exercise | Rats | Hippocampus | Adult rats: ↓ DNMT1 and DNMT3b; ↓ H3K9 methylation Aged rats: ↑ H3K9 methylation | [191] |
| Running wheel | Mice | Hippocampus | ↑ histone H4K8 acetylation at Bdnf promoters I and IV | [187] |
| Running wheel | Mice | Hippocampus and cerebellum | ↑ histone H3 acetylation in both regions; Cerebellum: ↑ HDAC2 and ↓ MeCP2, HDAC8 and DNMT1; Hippocampus: ↓ HDAC5, HDAC7, HDAC 8, DNMT1, DNMT3a, DNMT3b | [192] |
| Treadmill exercise | Rats | Hippocampus | ↑ histone H4 acetylation in aged rats | [193] |
| Treadmill exercise | Rats | Hippocampus | Exercise normalized stress-induced changes in histone H3 acetylation, HDAC5 and MeCP2 | [194] |
| Treadmill exercise | Rats | Frontal cortex | ↑ HAT activity; ↓ HDAC activity | [195] |
| Running wheel | Mice | Hippocampus | ↑ miR-28a-5p, miR-98a-5p, miR-148b-3p, miR-7a-5p and miR-15b-5p; ↓ miR-105, and miR-133b-3p | [196] |
| Running wheel | Mice | Hippocampus | ↑ 20 miRNAs and ↓ 12 miRNAs | [197] |
| Running wheel | Mice | Hippocampus | Exercise restored traumatic brain injury (TBI)-induced changes in miR-21 | [198] |
| Running wheel | Mice | Hippocampus | Exercise attenuated the increased expression of miR-124 in a stress model | [199] |
| Running wheel | Mice | Hippocampus | ↑ histone H3 acetylation at Bdnf promoters I, II, III, IV, VI and VII; ↓ HDAC5 expression in stressed mice | [200] |
| Swimming exercise | Mice | Hippocampus | ↑ H3K9, H3K14, H4K5, H4K8 and H4K12 acetylation; ↑ CBP expression | [201] |
| Running wheel | Mice | Basolateral amygdala | Exercise prevented the reduction in G9a histone methyltransferase expression induced by chronic stress; ↑ histone H3K9 dimethylation at oxytocin and vasopressin gene promoters | [202] |
| Running wheel | Mice | Hippocampus | ↓ HDAC2 and HDAC3 expression; ↓ HDAC2 and HDAC3 occupancy at Bdnf promoters | [188] |
| Treadmill exercise | Mice | hippocampus | ↑ HAT and HDAC activities | [203] |
| Running wheel | Rats | Hippocampus and frontal cortex | DNA hypomethylation; ↑ Tet1 and ↓ Dnmt3b expression | [204] |
| Treadmill exercise | Mice | Hippocampus | ↑ BDNF expression; ↓ HDAC activity, ↑ HAT/HDAC) | [205] |
| Aerobic, acrobatic, resistance, or combined exercise modalities | Rats | Hippocampus | Aerobic and resistance modalities attenuated age-induced effects on hippocampal Bdnf promoter H3K4me3. Exercise modalities modify H3K9ac or H3K4me3 at the cFos promoter | [206] |
| Forced running wheel | Mice | Hippocampus | Rescue the radiation-induced decrease of 5 hmC and BDNF expression | [207] |
| Treadmill exercise | Rats | Motor cortex | ↑ 5mC and 5hmC; ↑ Tet1, Tet2, and Tet3 expression | [208] |
| Treadmill exercise | Mice | Motor cortex | ↑ HDAC activity and acetylation level of histone H4 and H3 | [209] |
| Treadmill exercise | Mice | Hippocampus and hypothalamus | ↑ level of N6-methyladenosine (m6A) | [210] |
Exercise-induced epigenetic alterations
Emerging experimental and clinical evidence from animals and humans has indicated that exercise can induce epigenetic alterations, which may contribute to its beneficial impacts on health. For instance, acute exercise in human subjects induced a global DNA hypomethylation, which leads to an increased expression of key metabolic and regulatory genes, including PGC-1α, peroxisome proliferator-activated receptor δ (PPAR-δ), mitochondrial transcription factor A (TFAM), and myocyte enhancer factor 2 (MEF2), in an exercise intensities-dependent manner[211]. In addition, short-term exercise also results in decreased methylation of the PGC-1α promoter in human skeletal muscle and induces a dramatic increase in PGC-1α gene expression together with postexercise alterations of lipid metabolism[212]. Although the exact molecular mechanisms of how exercise induces epigenetic modifications are still far from being clearly elucidated, one recent study has suggested a possible involvement of calcium signaling[211]. No clear correlations have been observed between gene expression and DNA methylation, suggesting the possible involvement of other epigenetic mechanisms in exercise-modulated gene expression. There is also no conclusive relationship between global DNA methylation patterns and AD pathologies. Therefore, attention has been shifted to the effect of gene-specific methylation on the risk of AD.
Besides DNA methylation, exercise also induces histone modifications. A previous study reported that exercise increases histone 3 (H3) serine phosphorylation in the skeletal muscle of both untrained and trained subjects[213]. In animal studies, swimming exercise in rats increased H3 K9/14 acetylation, a histone mark associated with transcriptional activation, at the glucose transporter type 4 (Glut4) promoter in the triceps muscle[214]. Consistent with the histone modifications observed in muscles, a number of studies have also found histone modifications in various brain regions in response to exercise. For instance, forced swimming training promotes H3 K14 acetylation and serine 10 phosphorylation in the dentate gyrus of rodents in a time-dependent manner[215]. Moreover, voluntary exercise increases H3 acetylation at the BDNF promoter in the hippocampus of rats[216].
Exercise, epigenetic modulation on BDNF, and Alzheimer’s disease
More and more robust experimental evidence supports the positive impacts of physical exercise on psychiatric and neurological disorders, and epigenetic regulation of the BDNF gene has been recognized as an important biological mechanism by which exercise ameliorates neurological disorders[217,218], including AD. For example, peripheral levels of BDNF have been associated with cognitive function and hippocampal size in human subjects after exercise training[219,220]. Consistently, animal studies have also suggested the involvement of BDNF in the exercise-modulated expression of energy metabolism- and neurocognitive plasticity-related proteins in the hippocampus[221-222]. Specifically for AD, recent studies have identified the involvement of BDNF signaling in AD pathogenesis and the cognitive benefits of exercise on AD. Choi found that exercise provided cognitive benefit to 5 × FAD model mice of AD by inducing adult hippocampal neurogenesis and elevating BDNF levels[155]. In addition, chronic aerobic exercise can ameliorate Aβ-induced AD-like phenotype in rats through BDNF signaling[223].
As for the mechanisms involved in the BDNF-mediated benefits of exercise on AD, previous studies have indicated that exercise can modulate the activities of α-secretase and BACE1 through BDNF-mediated mechanisms, thereafter regulate APP processing and reduce Aβ production[224,225]. Moreover, exercise-induced epigenetic modifications of the BDNF gene, such as acetylation and methylation, have also been reported to play important roles[186-188]. For example, thirty days of voluntary running wheel training in mice induced hippocampal HDAC2 reduction, accompanied by the decreased interaction between HDAC2 and BDNF promoter I, leading to an increased BDNF expression[188]. Interestingly, the increased BDNF can further promote nitrosylation of HDAC2, resulting in increased histone acetylation in those BDNF target genes[226]. Despite the exercise-induced BDNF gene acetylation, Gomez-Pinilla et al. found that 7 days of running wheel exercise in rats reduced the level of DNA methylation in BDNF promoter IV in the hippocampus, accompanied by an elevated methyl-CpG-binding protein 2 (MeCP2) and increased BDNF mRNA and protein levels[186]. The elevated BDNF expression and cognitive improvement induced by exercise can be attenuated by the inhibition of Calcium-calmodulin-dependent protein kinase II[227,228].
Much more interestingly, BDNF transcription has been reported to be regulated by SIRT1-dependent deacetylation of MeCP2[229]. As mentioned above, SIRT1, beyond its complicated impacts on aging, stress tolerance, and metabolism, exerts key regulating activity on synaptic plasticity and memory formation. SIRT1-dependent deacetylation of MeCP2 permits its release from the methylated CpG site located in BDNF promoter IV and results in an increased BDNF transcription[229]. Moreover, SIRT1Δex4 mice exhibit significantly higher recruitment of MeCP2 on BDNF promoter IV, which was associated with decreased BDNF expression in hippocampus[229]. Consistent with these findings, treadmill running exercise in rats was found to increase SIRT1 activity in the hippocampus, together with increased BDNF and decreased apoptotic index[230]. In addition, treadmill running in ICR mice can also elevate SIRT1 and PGC1-α expression levels in various brain regions including cortex, hippocampus, hypothalamus, and midbrain, and[231]. Furthermore, the suppressed SIRT1 in the cerebral cortex of 3xTgAD mice was attenuated by treadmill exercise training[184].
As mentioned above, the exercise-modulated SIRT1 impacts the function of not only BDNF but also other enzymes involved in APP metabolism, including ADAM10 and BACE1, through epigenetic mechanisms. Activation of SIRT1 induces PGC-1α deacetylation, leading to the decreased BACE1 transcription and consequently reduction of Aβ production. SIRT1 also deacetylates and coactivates the retinoic acid receptor β, a known regulator of ADAM10 transcription, to promote the ADAM10-mediated non-amyloidogenic processing of APP[232]. Moreover, SIRT1 activation suppresses tau acetylation on K174 and reduces pathological tau propagation in the mouse models of tauopathy[233]. Taken together, exercise-induced SIRT1 activation may promote neurogeneration and plasticity and suppress the progression of AD pathologies through epigenetic modifications on targeted genes.
Exercise, microRNA and Alzheimer’s disease
miRNAs are important epigenetic modulating molecules involved in the beneficial impacts of exercise on AD. For example, miR-29 has been reported to be decreased in either AD patients[137] or transgenic AD model mice[234], and correlated with increased BACE1 levels. Progressive weighted wheel running in 3xTg-AD mice significantly increased this declined miR-29 level in the hippocampus and consequently reduced BACE1 level and Aβ burden[234]. Moreover, miR-34a has been reported to be upregulated in APP/PS1 transgenic mice[235,236]. Overexpression of miR-34a depresses ADAM10 expression and induces rapid cognitive impairment and AD-like pathologies[237], whereas knockout of miR-34a has been reported to modulate APP processing via inhibiting γ-secretase thereafter rescues cognitive deficits of APP/PS1 mice[238]. Interestingly, treadmill training can elevate miR-34a levels in mouse hippocampus[238]. Consistently, Kou et al. also found that swimming can attenuate autophagy dysfunction and abnormal mitochondrial dynamics via downregulating miR-34a, thus improving pathologies in aging-related diseases including AD[239]. Worth noting, miR-34a also targets and inhibits SIRT1[240,241], which is also involved in the exercise-induced AD improvements via PGC1-α/FNDC5/irisin/BDNF signaling, as described above.
MiR-132, another sncRNA with pivotal activity in neuronal development, structure and function, has been reported to regulate dendritic spine formation and maturation, so as to be involved in learning and memory. However, the modulating activity of miR-132 on cognition is controversial, because this effect is very dependent on its levels under physiological or pathological conditions. Lower[242] or higher[243] levels of miR-132 may be detrimental to cognition, while only moderate levels are beneficial[244]. It has been reported that acute intermittent exercise rapidly elevates circulating levels of miR-132 in healthy males[245]. In contrast, voluntary running wheel training can suppress the elevated hippocampal miR-132 level and ameliorate cognitive impairment in SAMP8 mice[246]. Consistently, swimming exercise reduced the increased miR-132 level in an ovariectomized rat model[247]. In addition, despite the direct modulating effects of miR-132 on cognition, previous studies have found an inhibiting effect of miR-132 on GSK-3β expression, leading to an ameliorated tau phosphorylation in hyperglycemia or chronic cerebral hypoperfusion animal model[248,249]. Moreover, miR-132-3p alleviates impairments of learning and memory abilities in AD-like homocysteine rat models by modulating the HNRNPU/BACE1 axis[250]. miR-132/212 deficiency led to cognitive impairment and tau hyperphosphorylation and aggregation in miR-132/212 knockout mice[251], promoting Aβ production and plaque formation in 3xTg AD mice[252]. These findings suggested that miR-132 is correlated with Aβ/tau pathologies of AD, which may provide further evidence supporting the positive impacts of exercise on AD through miR-132-related epigenetic mechanisms. Interestingly, the ameliorating effects of miR-132 on AD pathologies are also correlated with exercise-related SIRT1 signaling, suggesting a crosslink role of SIRT1 in miRNAs-mediated regulating effects against AD pathologies.
A previous study found that exercise reduces miR-146a level and increases miR-223 level in circulation in young healthy males[253]. As an NF-κB-sensitive miRNA, miR-146a has been reported to be elevated in AD and be closely associated with the proinflammatory state of AD[254-256]. This miRNA is correlated with the severity of AD[257] and involved in the progression of MCI to AD[258]. miR-223 is also a downstream molecule of NF-κB and is correlated with Nod-like receptor protein 3 inflammasome activation in AD[259,260]. miR-223 is downregulated in AD, either in serum of AD patients[261] or in AD cell models[262]. In turn, the lack of miR-223 leads to hippocampal-dependent contextual memory deficits and neuronal cell death[263].
CONCLUSION
Exercise plays important roles in brain health and cognition through various mechanisms, including elevated neurotrophins level, improved neurogenesis and neuroplasticity, restored angiogenesis and autophagy, and reduced neuroinflammation. In addition, exercise is also a vitally instrumental and daily-life remedy for reducing the susceptibility of brain to a wide range of neurological and neurodegenerative conditions, including AD. Recently, accumulating scientific evidence demonstrated the capacity of exercise to modulate genes and their protein products in the form of epigenomic manifestations. This promising impact of epigenetic mechanisms to regulate neuronal survival and plasticity has fundamental values to control or rescue pathological changes of AD [Figure 1].
Figure 1. Exercise ameliorates Alzheimer’s pathologies and cognition decline through epigenetic mechanisms. DNA and histone modifications and non-coding RNA profile alterations induced by various adverse environmental factors may result in elevated Aβ production, tau phosphorylation, neuroinflammation and neurodegeneration, and consequently participates in the cognitive decline and the pathogenesis of Alzheimer’s disease. In contrast, regular physical exercise can ameliorate these negative impacts caused by an aversive environment also through epigenetic mechanisms, thereafter directly or indirectly improving cognitive function and rescuing Alzheimer’s pathologies.
Following much deeper investigations in the future to reveal the exact spatial-temporal epigenetic modulating network by which exercise influences the expression or functions of AD-related genes and protein products, it will be clearer that epigenetic modifications by either pharmacological or
DECLARATIONS
Acknowledgments
The author would like to thank Professor Che Wang from Liaoning Normal University for her discussion and constructive comments during manuscript preparation.
Authors’ contributions
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Copyright
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Li S. Benefits of physical exercise on Alzheimer's disease: an epigenetic view. Ageing Neur Dis 2023;3:6. http://dx.doi.org/10.20517/and.2022.37
AMA Style
Li S. Benefits of physical exercise on Alzheimer's disease: an epigenetic view. Ageing and Neurodegenerative Diseases. 2023; 3(2): 6. http://dx.doi.org/10.20517/and.2022.37
Chicago/Turabian Style
Li, Song. 2023. "Benefits of physical exercise on Alzheimer's disease: an epigenetic view" Ageing and Neurodegenerative Diseases. 3, no.2: 6. http://dx.doi.org/10.20517/and.2022.37
ACS Style
Li, S. Benefits of physical exercise on Alzheimer's disease: an epigenetic view. Ageing. Neur. Dis. 2023, 3, 6. http://dx.doi.org/10.20517/and.2022.37
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