ReviewNutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of dementia worldwide. Pathologically, AD is characterized by senile plaques consisting of extracellular deposits of β-amyloid (Aβ) peptide and intraneuronal neurofibrillary tangles (NFTs) due to hyperphosphorylation of tau protein (DeTure and Dickson 2019). Several other pathophysiological mechanisms such as neuroinflammation, oxidative stress, and mitochondrial dysfunction are also implicated in the pathogenesis of AD (Fan et al., 2020). Mitochondrial dysfunction resulting in energy deficiency is an essential mechanism in the initial stages of AD. Various studies have investigated the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of AD (Ramesh et al., 2018a). Swerdlow and Khan proposed the mitochondrial cascade hypothesis to explain late-onset, sporadic AD in which mitochondrial dysfunction is the primary event that causes Aβ deposition, NFTs formation, and synaptic degeneration (Swerdlow and Khan 2004; Swerdlow et al., 2010).
The mitochondrial dysfunction seen in AD could be attributed either due to glucose hypometabolism leading to impaired oxidative phosphorylation (Crane et al., 2013; Kapogiannis and Mattson 2011), impaired oxygen metabolism leading to impaired electron transport chain (ETC) in the mitochondria (Watts et al., 2018), impaired bioenergetics machinery (tricarboxylic acid cycle and the ETC chain) (Brooks et al., 2007), reductions of mitochondrial complexes activity (Adav et al., 2019) or mutations in mitochondrial DNA (mtDNA) which promote mitochondrial genomic dyshomeostasis (Chen et al., 2016). Mitochondria contribute approximately 90% of cellular reactive oxygen species (ROS) and excess ROS formation lead to oxidative stress (Balaban et al., 2005). Interestingly, mitochondria are vulnerable to oxidative damage and dysfunctional mitochondria produce less ATP and more ROS. Therefore, increased oxidative stress could be both the cause and consequence of mitochondrial dysfunction (Wang et al., 2020).
Sirtuins represent a conserved family of proteins present in almost all life forms that act as NAD + -dependent protein deacetylases. It was first identified in brewer's yeast S. cerevisiae wherein it delayed aging by gene silencing mechanisms and was thus termed silent information regulator 2 (SIR2) (Giralt and Villarroya 2012). Sirtuins are important in maintaining normal cellular functions, regulating cellular aging and/or senescence, and acting as an epigenetic regulator of cell functions. Sirtuins are divided into five subclasses based on the conserved catalytic core domain. Class I is comprised of SIRT1, 2, and 3, which exhibit robust deacetylase activity. SIRT4, a class II Sirtuin and functions predominantly as an ADP-ribosyltransferase in mitochondria. SIRT5 belongs to Class III, while SIRT6 and 7 are assigned to Class IV. The U class sirtuins have only been observed in bacteria. Another classification of sirtuins is based on their specific sub-cellular localizations and can be classified into seven types, SIRT1-7, in mammals. SIRT1, SIRT6 and SIRT7 are predominantly located in the nucleus and promote cell survival by deacetylating several transcription factors (Pillai et al., 2010). SIRT2 is in the cytoplasm and mediates oxidative stress resistance and cell division (North 2003; Wang et al., 2007). SIRT3, SIRT4, and SIRT5 are mitochondrial proteins that act as stress sensors. Specifically, they regulate several other mitochondrial proteins to maintain homeostasis during insult, such as increased oxidative stress, mitochondrial bioenergetic failure, dysregulated energy regulation and metabolism, apoptosis, and cell death (Verdin et al., 2010). Among the mitochondrial sirtuins, SIRT3 is the main mitochondrial NAD + -dependent deacetylase (Lombard et al., 2007), and it regulates mitochondrial metabolism, including the tricarboxylic acid (TCA) cycle, the urea cycle, amino acid metabolism, fatty acid oxidation, ETC/oxidative phosphorylation (OXPHOS), ROS detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR) (Papa and Germain 2017; Samant et al., 2014).
The SIRT3 protein is widely expressed in mitochondria-rich tissues, such as the kidneys, heart, brain, and liver tissue, and are known to exert several biological activities, including metabolic control (Jin et al., 2009; Shi et al., 2005), neuroprotection (Kong et al., 2010), cardiovascular disease (Koentges et al., 2016), cancer (Alhazzazi et al., 2011), and aging (Bellizzi et al., 2005). The SIRT3 gene in humans is a 399 amino acid protein synthesized in the inner mitochondrial membrane as an enzymatically inactive protein. The full length SIRT3 gene has a predicted molecular weight of 44 kDa with a 25 amino acid mitochondrial localization sequence at its N-terminus (Onyango et al., 2002; Schwer et al., 2002). In the mitochondrial matrix, the full-length form is cleaved to a 28 kDa active and mature form by matrix peptidase, which activates its deacetylase activity (Smith et al., 2008). In comparison to human SIRT3, mouse SIRT3 is a 257 amino acid protein and corresponds to 143–299 residues of human SIRT3 (Yang et al., 2000). This form of mouse SIRT3 lacks the N-terminal 142 amino acid residues necessary for the mitochondrial localization in the human counterpart, although both mitochondrial targeting and nuclear localization signal sequences have been identified in 143–165 aa and 278–302 aa, respectively, in this form of murine SIRT3 protein (Nakamura et al., 2008).
As chronic inflammation plays a key role in the pathogenesis of AD, there has been a recent interest in studying the role of several infections and the risk of AD (Sochocka et al., 2017). Chronic and persistent infections by neurotrophic microbial agents, for instance viruses such as herpes virus, cytomegalovirus, varicella-zoster, and Epstein-Barr virus, can trigger chronic neuroinflammation and the susceptibility to develop AD (Baudron et al., 2015; Bu et al., 2015). The hypothesis is based on several studies which showed herpes DNA in AD brains at higher rates than controls and the co-localization of herpes DNA with amyloid plaques in AD brains in comparison to control brains (Itzhaki 2014; Itzhaki et al., 2016; Wozniak et al., 2009). The evidence is based on the fact that several viruses target mitochondrial functions in different ways to establish a proliferative function and then disseminate by killing the cells (Tiku et al., 2020). Additionally, the downstream of infection such as exaggerated immune responses and inflammation can strongly impact the mitochondria structurally and functionally. Although the investigations of mitochondrial sirtuin functions during viral infection have only recently emerged and are still limited, the interface between SIRT functions, dynamic changes in metabolism, and viral infection hold significant promise to understanding both the biology and pathogenicity of infections. Thus, it will be interesting to infer this recent insights and explore into how these fundamental processes governed by mitochondria can be translated into active therapeutics. SIRT3 has been proposed to be a promising therapeutic target for neurodegenerative diseases such as AD, and a series of natural compounds targeting SIRT3 have displayed favorable therapeutic effects. In this review, we focus on summarizing the role of SIRT3 activators and their potential applications in AD.
Several natural products are used to influence the activity of SIRT3 in Alzheimer's disease. The following sections describe the several positive activators or modulators of SIRT3 reported.
Section snippets
Honokiol
Honokiol is one of the most studied SIRT3 activators that increases SIRT3 expression and deacetylation activity. Honokiol [2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol] is a bioactive compound obtained from Magnolia grandiflora and possesses multiple properties including anti-oxidative, anti-inflammatory, anti-tumor, anti-arrhythmic, antithrombocytic, anti-angiogenic, and anxiolytic activities (Arora et al., 2012; Chen et al., 2010; Sulakhiya et al., 2014). Honokiol crosses the blood
Dihydromyricetin
Dihydromyricetin (DHM), also known as Ampelopsin ((2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one; AMP) is a flavanonol and is the primary bioactive ingredient of the Chinese medicinal herb Ampelopsis grossedentata (Hand-Mazz) W.T. Wang. DHM has been shown to possess anti-oxidative, anti-inflammatory, anticancer, and anti-alcohol intoxication effects (Li et al., 2017a; Shen et al., 2012). Furthermore, DHM has been shown to exert neuro-protective effects by
Trans ε-viniferin
Trans ε-viniferin (viniferin) is a natural polyphenol stilbenoid present in vine stalks and most woody parts of the vine. This stilbenoid corresponds to a dehydrodimer of resveratrol and can exhibit superior properties than those observed with resveratrol. It is synthesized by Vitis vinifera in response to different stresses. SIRT3 is a NAD dependent deacetylase sirtuin-3predominantly found in the mitochondria, which is highly expressed in the brain. It was found that deletion of SIRT3 in mice
Adjudin
Adjudin is also known as 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbo-hydrazide (Mok et al., 2011). Adjudin was initially developed as an analogue of lonidamine to serve as a non-hormonal reversible male contraceptive by exfoliation of the immature sperms from the seminiferous tubules. Currently, multifunctional adjudin has been developed as an anti-cancer drug and an anti-inflammatory drug that can possibly help in neuroprotection. Exceptionally, adjudin can result in the activation of
Trilobatin
Trilobatin is a small molecule glycosylated dihydrochalcone bioactive compound isolated from Lithocarpus polystachyus Rehd, a traditional Chinese folk medicine (Wang et al., 2016). Trilobatin has been shown to exert multiple pharmacological properties including antioxidative properties (Gao et al., 2018), anti-diabetes mellitus (Liu et al., 2020), anti-inflammation (Zhong et al., 2020), and anti-HIV-1 activity (Yin et al., 2018). Trilobatin binding to SIRT3 was determined by computational
Salidroside
Salidroside is widely used in traditional Chinese medicine and is the major active ingredient extracted from Rhodiola rosea. It has been shown to exert anti-inflammatory, anti-oxidative, and anti-autophagic effects. Salidroside increases the expression of SIRT3 and has been shown to attenuate cellular senescence (Xing et al., 2018). We validated these findings by determining the docking score of Salidroside to SIRT3 protein by computational analysis. Salidroside had a glide ligand docking score
Miscellaneous compounds with SIRT3 activity
A growing number of reports indicate that several other drugs or compounds are known to possess SIRT3 activity as summarized in Table 2. Metformin is a known AMPK activator used to improve insulin resistance in type 2 diabetes mellitus patients. A recent study by Karnewar et al. showed that metformin increases SIRT3 activity and delays endothelial senescence and vascular aging (Karnewar et al., 2018). Though metformin has been extensively studied both in vitro and in vivo models of AD, its
Conclusions and future directions
The dysregulation of SIRT3 has been confirmed in neurodegenerative diseases such as AD. Several areas of research have demonstrated in the previous decades that SIRT3 activators present neuroprotective actions in experimental models of AD. This review focused upon the neuroprotective effects of several natural SIRT3 activators and described various mechanisms which are likely to mediate the neuroprotective effects of these compounds. Further studies need to be done to evaluate the
Funding
This research received no external funding.
CRediT authorship contribution statement
Manoj Govindarajulu: Conceptualization, Writing - original draft, Writing - review & editing. Sindhu Ramesh: Conceptualization, Writing - original draft, preparation. Logan Neel: Investigation, Software, (computational docking). Mary Fabbrini: Writing - original draft. Manal Buabeid: Writing - original draft. Ayaka Fujihashi: Writing - original draft, Writing - review & editing. Darby Dwyer: Writing - original draft. Tyler Lynd: Writing - original draft. Karishma Shah: Writing - original draft.
Declaration of competing interest
The authors declare no conflicts of interest.
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