The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease

Abstract

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease.

Keywords

Alzheimer’s disease mitochondrial autophagy protective mechanism SIRT1

INTRODUCTION

Sirtuins are nicotinamide adenine dinucleotide-dependent (NAD⁺) deacetylases that have traditionally been associated with caloric restriction and aging in mammals. These proteins are beneficial in maintaining the healthy state of neurons during aging. Silent information-regulated transcription factor 1 (SIRT1) is a class III NAD⁺-dependent histone deacetylase [1, 2]. SIRT1 is widely expressed in the brain and is involved in a variety of physiological activities such as aging, stress, and energy metabolism [3, 4]. It has been found that the inhibition or knockout of SIRT1 may cause neurodegeneration in aged mice, while an increase in the protein expression of SIRT1 could significantly alleviate the central neuroinflammatory response induced by injurious stimuli [5, 6]. SIRT1 is expressed in both the neurons and glial cells. The protein expression of SIRT1 in the microglia of aged mice has been seen to be significantly lower than in adult mice, and the reduced protein expression of SIRT1 in the microglia may cause upregulation in the expression of proinflammatory factor interleukin 1 beta [7]. SIRT1 may induce nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) deacetylation, thereby inhibiting the NF-κB-mediated inflammatory responses, and the reduction in SIRT1 expression may simultaneously cause increased NF-κB-mediated inflammatory responses [8, 9]. It has been found that the reduced protein expression of SIRT1 in microglia may lead to reduced DNMT1 activity, which may cause upregulation in the expression of downstream interleukin 1 [7]. In neurons, SIRT1 is involved in regulating synaptic plasticity, and SIRT1 acts on tau protein to achieve deacetylation, which can reduce the pathological diffusion of tau protein, thus maintaining synaptic and neuronal functions [10, 11].

SIRT1, the gene of which is located on chromosome 10, is highly conserved in both mice and humans. The human SIRT family encodes seven genes belonging to I–IV (SIRT1–7) [12], of which SIRT1 is the homolog with the greatest homology with the yeast silent information regulatory protein 2 found in mammalian cells, and it is the most characteristic class of deacetylases among the members of the SIRT family. These enzymes were originally identified as gene silencers in yeast, and they act on histones and other substrates in the presence of NAD⁺. SIRT1 can regulate many important downstream genes and enzymes and affect physiological activities such as energy metabolism. The main function of SIRT1 is the acetylation and deacetylation of substrates, which are the most important of many covalent modifications and play a key role in transcription regulation.

Although there is some debate concerning the exact role of sirtuins in caloric restriction and aging, the important role of these proteins in both processes has been reemphasized in many studies published in recent years [13]. Sirtuins contribute greatly to neural development, affecting the brain structure through changes in axon elongation, spine growth, dendritic branching, and the cell cycle of neuronal precursor cells. These proteins play an essential role in the hypothalamic regulation of circadian rhythms, endocrine function, and feeding behavior. It has been suggested that SIRT1 may also be instrumental in regulating synaptic plasticity and memory formation in the adult brain [14, 15]. In addition to its significant function in normal brain aging, SIRT1 may be able to alleviate the effects of neurodegenerative diseases including Alzheimer’s disease (AD) [11 , 17], Parkinson’s disease [18], Huntington’s disease [19, 20], motor neuron disease [21], and multiple sclerosis [22]. In studies in animal models of these neurological diseases, for which no effective therapy has yet been found, it has been suggested that SIRT1 plays an important role. AD is an age-related neurodegenerative disease in which the accumulation of amyloid-β and senile plaques, neurofibrillary tangles, and granular vacuolar degeneration are visible in the brain with the most severe injury occurring in the hippocampal and parahippocampal regions. Therefore, investigation of the sirtuin pathway may be beneficial in finding new targets for the treatment of AD, and the results of such a study could have important theoretical implications and potential economic and social benefits.

Resveratrol, an activator of SIRT1, has been shown to directly activate the enzyme through a variable configuration site near the catalytic structural domain. Resveratrol inhibits the Cyclic Adenosine monophosphate (cAMP)-degrading phosphodiesterase and activates the CaMKKb-AMPK pathway by increasing the level of cAMP and activating Epac1. In addition to increasing the intracellular calcium levels, this pathway also increases the activity of NAD⁺ and SIRT1 [23]. In the present review, we shall summarize the progress of studies into the SIRT1 regulation of mitochondrial biogenesis and the involvement of mitochondrial autophagy in the protective mechanisms for AD.

THE EFFECTS OF SIRT1 ON THE STRUCTURE OF AGING NEURONS IN THE NORMAL BRAIN

SIRT1 is a deacetylase that is involved in the regulation of a variety of physiological activities including brain development, aging, stress response, inflammation, and cancer [4 , 25]. It is widely distributed in the brain and is involved in regulating synaptic plasticity and memory formation [14, 15]. It may also maintain physiological brain function and mediate caloric restriction, exerting anti-aging and neuroprotective effects. In addition, the expression of SIRT1 is significantly downregulated in many neurodegenerative diseases such as AD, Huntington’s disease, and Parkinson’s disease [19 , 27].

Early neuronal development begins with axonal extension growth followed by axonal differentiation, dendritic branching, and the formation of synapses [28]. SIRT1 has been shown to promote axonal extension growth, and the sub-cellular localization of SIRT1 deacetylase plays a critical role in biological functions. One study concerning PC12 cells suggested that cytoplasmic SIRT1 may have stimulated the growth of nerve growth factor (NGF)-dependent neural protrusions. However, this effect was no longer seen when the nuclear-localization structures or catalytically inactive mutants were analyzed [29]. According to one study, the inhibition of SIRT1 may reduce neuronal axon elongation in the brain [30], and it was demonstrated in another that the elongation of neural axons, neuronal activity, and the downregulation of the mechanistic target gene of rapamycin (mTOR) were interlinked [31].

In 2013, Li et al. [32] suggested that SIRT1 could promote axon elongation by deacetylating Akt and inhibiting glycogen synthase kinase 3 (GSK-3), thereby affecting microtubule dynamics during axon elongation. SIRT1 may also interact with microRNA-138 (miR-138) through a negative feedback loop, and microRNAs can inhibit axon growth. The cytoplasmic SIRT1 may stimulate the NGF-dependent elongation of neural axons due to the inhibition of the downregulation of the downstream effects of mTOR [31].

SIRT1 may also promote the development of axons in embryonic hippocampal neurons. It is known that SIRT1 can activate Akt, the upstream inhibitory kinase of the GSK-3, and promote axon growth in cultured hippocampal neurons [32]. In embryonic cortical neurons, SIRT1 is the target of miR-138, which is a small non-coding RNA molecule that inhibits axonal growth [33]. SIRT1 is also able to inhibit miR-138, thus counteracting any injury to the peripheral nerve and forming a negative feedback loop.

THE REGULATION OF HIPPOCAMPAL LEARNING AND MEMORY BY SIRT1

Synaptic plasticity plays an important role in the formation of learning and memory, and sirtuins are involved in the active mechanism of this process. In the SIRT1 knockout animal model, the morphological structure of neurons was altered, and Golgi staining showed a reduction in dendritic branching [15]. The morphology of synapses was observed using electron microscopy, and it was found that the inhibition of SIRT1 reduced the number of synapses in hippocampal neurons [34].

Synaptic plasticity was reduced in brain-specific SIRT1 knockout mice. It appears that SIRT1 may interact with a blocking complex containing the transcription factor YY1 and the YY1 transcriptional regulator microRNA-134 (miR-134), a brain-specific small RNA that may regulate the expression of cAMP response binding protein (CREB) and brain-derived neurotrophic factor (BDNF) [14]. SIRT1 may affect synaptic plasticity through a repressor complex containing the transcription factor YY1. The YY1 transcription factor may regulate miR-134, while this brain-specific microRNA may regulate the expression of CREB and BDNF [14], thus playing an important role in synapse formation and long-term potentiation (LTP). The SIRT1 knockout mice had impaired hippocampus-dependent memory, which was correlated with the decreased LTP in the hippocampal CA1 area [14, 15].

A subsequent study verified the reproducibility of these changes by pharmacological methods and found that the levels of miR-124 and miR-134 decreased after treatment with resveratrol [35]. Both CREB and BDNF were higher at the time of memory formation, while LTP was stronger in the resveratrol-treated animals [35].

SIRT1 AND MITOCHONDRIA

The mitochondrial localization of SIRT1

SIRT1 is mainly found in the nucleus of most types of cells [36], which makes it a true histone deacetylase [37] and a deacetylated histone modification enzyme similar to histone methyltransferase SUV39H1 [38]. Most functions of SIRT1 are related to the deacetylation of transcription factors. As with all nuclear proteins, SIRT1 is synthesized in the cytoplasm and enters the nucleus. SIRT1 is a NAD⁺-dependent histone deacetylase that is involved in the regulation of life processes such as DNA repair, apoptosis/cell survival, cell differentiation, endocrine signaling pathways, and aging due to deacetylation. SIRT1 improves insulin sensitivity and decreases insulin resistance by regulating the interaction between insulin-related proteins and insulin signaling pathways in insulin-sensitive tissues and organs. The role of SIRT1 in mitochondrial injury is closely correlated with the development of insulin resistance.

Both SIRT1 and the nuclear transcription factor PGC-1α are present in the mitochondria of human cell lines and platelets and in various organs in mice. SIRT1 and its substrate, PGC-1α, may regulate energy metabolism through the mitochondria, but energy metabolism was initially thought to occur as a result of nuclear-localized transcription [2, 39].

The relationship between SIRT1 and PGC-1α proteins in the regulation of mitochondrial function

Mitochondria are the sites of energy production by biological oxidation in living cells, and they are the energy converters of the cell. The genes of mitochondrial DNA (mtDNA) are highly dependent on nuclear genes for transcription and translation, which act together in the regulation of body metabolism. mtDNA is located near the inner mitochondrial membrane and is directly exposed to the superoxide ions generated by respiratory chain metabolism and the hydroxyl radicals generated by electron transfer. Therefore, it is highly susceptible to oxidative injury. The mitochondria in all cells are constantly renewed. However, the homeostasis of the number of mitochondria reflects the dynamic balance between mitochondrial biogenesis and autophagy [40, 41]. Mitochondrial biogenesis involves the transcription of genes encoded by the nucleus and mtDNA and is regulated by the peroxisome proliferator-activated receptor-1 (PGC-1) family of transcriptional co-activators [42].

With regard to the importance of the status of SIRT1 acetylation for the cellular activity of PGC-1, the relationship between SIRT1 and PGC-1α has been the focus of studies on metabolic regulation and mitochondrial biogenesis. Finkel’s team demonstrated that SIRT1 may functionally interact with PGC-1α [43]. Both SIRT1 and nuclear transcription factor PGC-1α are present in the mitochondria of human cell lines and platelets and in various organs in mice. In mitochondria, both deacetylases and substrates are associated with mtDNA-like nuclei and mitochondrial transcription factor A [44]. These studies indicated that the transcription of SIRT1 and PGC-1 may directly affect mitochondrial transcription. However, the functions of mitochondrial SIRT1 and PGC-1 in this regard remain unclear.

Auwerx et al. found that poly [ADP-ribose] polymerase-1 (PARP-1) is an important NAD⁺-depleting enzyme, and the absence of PARP-1 leads to increased SIRT1 activity. The PARP-1 knockout mice had increased mitochondrial content and energy expenditure and were protected against metabolic diseases [45]. The work of Anderson et al. [46] provided insights into the dynamic regulation by SIRT1 on the action of PGC-1α. They concluded that the nuclear-transcriptional activity of PGC-1α was enhanced by the accumulation of SIRT1 in the nucleus but could be inhibited by the glycogen synthase kinase GSK3β. GSK3β may target PGC-1α to allow the degradation of the intranuclear proteasome.

Despite the apparent functional link between SIRT1 and PGC-1α, it is still uncertain whether SIRT1 plays a role in mitochondrial biogenesis. The effects of resveratrol on PGC-1α and mitochondrial biogenesis and the mode of involvement of AMPK have also been disputed [47]. However, an induced knockout mice model was used by the Sinclair team to demonstrate that SIRT1 was necessary for the maintenance of mitochondrial biogenesis and functional activity [48].

SIRT1 and mitochondrial autophagy

Following on from the discussion of the role of SIRT1 in mitochondrial biogenesis, it has been found in several studies that SIRT1 is also involved in the process of destroying injured or aged mitochondria through mitochondrial autophagy [49]. Mitochondrial autophagy is dependent upon two factors: Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. These proteins can sense mitochondrial function and health status and mark injured mitochondria for mitochondrial autophagy [50]. The regulation of autophagy by SIRT1 is well known [51] and widely recognized as a protective mechanism for cells in response to stress and death [52, 53]. The link between SIRT1 and autophagy was first proposed by Hwang’s study group, which found that treating primary human fibroblasts with nicotinamide significantly extended the replicative lifespan by accelerating the autophagic degradation of mitochondria [54]. Nicotinamide decreased the mitochondrial mass, increased the mitochondrial membrane potential with increased autophagosome marker light chain 3 II, and increased the expression of proteins that regulate mitochondrial fusion and division [55].

Nicotinamide can be converted to NAD⁺ by the salvage pathway of NAD⁺ synthesis. It was pointed out by Hwang et al. that the autophagic effect of nicotinamide was mediated by increasing the NAD⁺/NADH ratio and SIRT1 activation [56], and the nicotinamide-induced mitochondrial phenotype could be mimicked by the SIRT1 activator SRT1720. The SIRT1 activator resveratrol acts through the SIRT1-SIRT3-involved, PINK1/Parkin-mediated autophagic signaling pathway resulting in a cardioprotective effect [57].

SIRT1 activity can have important effects on mitochondrial function, but the extent of the effect may be correlated with the cell type and the physiological environment. The activation of SIRT1 can promote mitochondrial biogenesis under conditions of energy deficiency associated with disease and injury but may also play an important role in triggering the death or replacement of injured mitochondria.

The accumulated evidence demonstrated that autophagy is usually considered to be a protective process that prepares cells to survive under various stress conditions [56]. The mitophagy-dependent PINK1/Parkin pathway is thought to maintain mitochondrial quality by eliminating damaged mitochondria, which is regarded as a defense mechanism of the mitochondrial function. The activation of autophagy/mitophagy contributes to removing the damaged or redundant organelles’ metabolites and maintaining cell homeostasis. It has been suggested that SIRT1, autophagy, mitophagy, or oxidative stress may be an effective potential target and research design area for intestinal stress injuries (see Fig. 1).

Fig. 1

Schematic illustration of SIRT1/PGC-1α on stress, autophagy, and mitophagy. Stress and injury resulted in autophagy/mitophagy elevation. SIRT1/PGC-1α pathway activation might be a protective mechanism against oxidative stress-mediated ROS. Intracellular and particularly the nuclear levels of NAD are believed to increase and lead to activation of Sirt1 enzymatic activity in the setting of low nutrient availability. SIRT1 may contribute to cellular function regulation by deacetylating PGC-1α and being involved in energy management, mitochondrial biogenesis, and various physiological processes including aging and stress response. SIRT1/PGC-1α pathway activation could be caused by agonists SRT 1720, leading to a significant decrease of ROS and an elevation of mitochondrial membrane potential. Stress and injury significantly activated autophagy markers including LC3 and Beclin 1, and p62 expression level was inhibited. Also, PINK1/Parkin dependent-mitophagy is one of the main pathways contributing to maintain the homeostasis and quality control of mitochondria.

SIRT1 AND AD

AD is a progressive, degenerative disease of the nervous system with an insidious onset. Worldwide, the number of people with dementia is increasing, and AD is the most common cause of cognitive impairment [55]. Clinically, AD is characterized by a comprehensive spectrum of dementia including memory impairment, aphasia, apraxia, cognitive impairment, visuospatial skill impairment, executive function impairment, and personality and behavioral changes, the causes of which are still unknown. However, it appears that oxidative stress and mitochondrial dysfunction play an important role in the development of AD. Amyloid-β can induce the release of reactive oxygen species (ROS) and inflammatory factors from microglia and astrocytes, and ROS can destroy membrane phospholipids, proteins, DNA, RNA, and other macromolecules, which leads to a loss of function and the release of cytochrome C, which induces apoptosis. Familial AD is an autosomal dominant neurological disorder associated with mutations in the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2).

Aβ, with a molecular weight of approximately 4 kDa, is a polypeptide composed of 39–43 amino acids produced from the amyloid-β protein precursor (AβPP) by the proteolytic action of β- and γ-secretase. The most common subtypes of Aβ in humans are Aβ_1–40 and Aβ_1–42. In human cerebrospinal fluid and blood, the levels of Aβ_1–40 are 10 and 1.5 times higher than those of Aβ_1–42, respectively. Aβ_1–42 is more toxic and aggregates more easily, thus forming a core of Aβ deposits and triggering neurotoxic effects. Tau proteins also accumulate abnormally during the pathogenesis of AD and form intracellular neurofibrillary tangles.

Initially, in studies on related cell lines [58, 59] and hippocampal neurons [60], resveratrol was found to reduce Aβ-induced cytotoxicity, thus increasing the probability that sirtuins may be involved in ameliorating the pathophysiological mechanisms of AD. In vivo experimental studies showed that resveratrol could reduce plaque formation in a transgenic AD mouse model [61, 62].

To link sirtuins more clearly to reducing amyloid toxicity, it was observed that the expression of microglia NF-kB was reduced and Aβ neurotoxicity was decreased by a SIRT1 lentivirus infection [18]. Evidence for the idea that the overexpression of SIRT1 may reduce plaque formation and improve behavioral phenotypes was obtained from in vivo experiments with an APP/PS1 mouse model.

Pathologic hallmarks of AD include senile plaques comprising Aβ proteins along with many other misfolded proteins and neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates. Anti-Aβ and anti-tau proteins are the main directions for research and development [63]. The exact pathogenesis of AD has not yet been clarified, and there are still no methods or drugs to cure AD. At present, the research into drugs for the treatment of AD is multidirectional including using anti-inflammatories [64], improving metabolism [65, 66], improving vascular function [67], and using combination therapy. The dual goals in the treatment of AD are to reduce the deposition of neurotoxic Aβ peptide in the brain and increase the rate of repair of injured neurons, and SIRT1 could mediate both processes by deacetylating the transcription factor retinoic acid receptor β, which is a new target for AD therapy [16].

A mouse model expressing a p25 mutation [68] and a tau transgenic mouse model expressing a P301L mutation [11] were used by researchers to demonstrate that SIRT1 might improve the phosphorylation of tau proteins with consequent effects on the onset of cognitive impairment and mortality. During the early stages of the disease, tau proteins are acetylated in multiple residues, and deacetylation by SIRT1 may allow ubiquitin ligases to target tau proteins in order to promote the clearance of these proteins rather than allowing their pathological intracellular aggregation [11, 69].

An important pathological indication in the brains of patients with AD is the presence of neurofibrillary tangles caused by both extracellular Aβ plaques and intracellular tau protein accumulation. Studies concerning AD support the possibility that SIRT1 may affect Aβ deposition as well as tau protein phosphorylation. However, more research is needed to determine whether SIRT1 activators can be used to treat patients with AD.

Next-generation sequencing has been adopted by researchers to analyze the genes associated with AD, and the APP, PSEN1, and PSEN2 genes have been sequenced. The mutations of these genes have been identified as the cause of early-onset AD. More work is needed to investigate whether SIRT1 activators can be used to treat AD. Further validation of the effectiveness of using different SIRT1 activators (including preparations of resveratrol) in the clinical treatment of patients with AD is needed in future clinical trials. It has been shown that resveratrol can also reduce the formation of plaque in a transgenic AD mouse model [61, 62]. It is more widely believed that the link between SIRT1 and neurodegenerative diseases may not be an autophagy factor but a PGC-1α [70, 71].

CONCLUSION

In the present review, the protective mechanisms of SIRT1 in the regulation of mitochondrial biogenesis and the involvement of autophagy in AD were discussed [72]. SIRT1 may affect the morphology of neurons during development and maintain the dynamic balance of metabolism and circadian rhythms during aging. Due to the hypothalamic and peripheral effects of SIRT1, modulation of SIRT1 activity may be an effective strategy for the treatment of diabetes mellitus and obesity and a promising therapeutic target for neurodegenerative diseases.

In summary, SIRT1 could simultaneously regulate mitochondrial biogenesis and autophagy and play a role in maintaining the quality of mitochondria. Numerous potential regulatory profiles of SIRT1 could be used to treat neurodegenerative diseases, but a better understanding of the molecular mechanisms of the interactions is necessary.

SIRT1 may be a valuable target for the treatment of neurodegenerative diseases. However, further research is necessary to determine the safety and effectiveness of certain sirtuin activators. An exciting new finding [72, 73] in the field of research on cellular aging is that the expression level of NAD⁺, the common substrate of SIRT1–7, decreases with age in mice [72, 73], rats [74], nematodes [72], and humans [75].

A decrease in NAD⁺ would decrease the activity of SIRT1–7, and therefore, the protective effect against neurodegenerative diseases would decrease. Supplementing diet with NAD⁺ precursors such as nicotinamide mononucleotide or nicotinamide riboside restores the level of NAD⁺ in aging mice. Some studies have suggested that sirtuin activators combined with NAD⁺ supplementation may offer a new therapeutic approach to combating neurodegenerative diseases.

Stress and injury resulted in an increase in autophagy/mitophagy. SIRT1/PGC-1α pathway activation may be a protective mechanism against oxidative stress-mediated ROS. Intracellular, and particularly nuclear, levels of NAD are believed to increase and lead to the activation of SIRT1 enzymatic activity in a setting of low nutrient availability. SIRT1 may contribute to cellular function regulation by deacetylating PGC-1α and is involved in energy management, mitochondrial biogenesis, and various physiological processes including aging and stress response. SIRT1/PGC-1α pathway activation could be caused by the agonist SRT1720 leading to a significant decrease in ROS and an elevation in the mitochondrial membrane potential. Stress and injury significantly activated autophagy markers including LC3 and Beclin 1, and p62 expression level was inhibited. In addition, PINK1/Parkin-dependent mitophagy is one of the main pathways contributing to maintaining homeostasis and quality control of the mitochondria.

Footnotes

ACKNOWLEDGMENTS

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

This study was supported by the National Natural Science Foundation of China (Grant No. 81771139), Beijing Natural Science Foundation (Grant No. 7194270).

Authors’ disclosures available online ().

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