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Resveratrol has multiple biological functions that are relevant for AD. Resveratrol acts on the neuropathological hallmarks of AD via multiple routes. Resveratrol inhibits the expression of MID1, thereby activating PP2A and dephosphorylating Tau. Additionally, MID1 induces the PP2A opposing kinase mTOR. Resveratrol induces degradation pathways by inhibiting mTOR signalling and inducing AMPK, thereby stimulating the clearance of Aβ. Resveratrol inhibits BACE1, resulting in decreased Aβ production. Resveratrol induces ADAM10, resulting in a preferential cleavage of APP via the non-amyloidogenic pathway.
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The formation of paired helical filaments (PHF), which are composed of hyperphosphorylated Tau protein dissociating from microtubules, is one of the pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. The most important phosphatase that is capable of dephosphorylating Tau at AD specific phospho-sites is protein phosphatase 2 A...
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Context 1
... and the subsequent destabilization of its mRNA, resvera- trol reduces MID1 expression, which is followed by a significant increase of microtubule-associated PP2A activity (shown by a decrease of phosphorylation of the PP2A targets S6K and S6). PP2A leads to the dephosphorylation of the microtubule-associated Tau protein at PP2A specific sites (Fig. 6). Therefore, our data support a beneficial role of resveratrol in AD ...
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Citations
... However, herein, we show that resveratrol treatment resulted in reduced levels of phosphorylated Tyr307 on PP2A, the inhibitory site, thereby increasing the activity of PP2A. This effect of resveratrol on PP2A has also been documented in several recent publications [16,22,23]. ...
... However, herein, we show that resveratrol treatment resulted in reduced levels of phosphorylated Tyr307 on PP2A, the inhibitory site, thereby increasing the activity of PP2A. This effect of resveratrol on PP2A has also been documented in several recent publications [16,22,23]. However, these studies did not measure AMPK activation in parallel. ...
Resveratrol is a polyphenol known to have metabolic as well as circadian effects. However, there is little information regarding the metabolic and circadian effect of resveratrol on muscle cells. We sought to investigate the metabolic impact of resveratrol throughout the circadian cycle to clarify the associated signaling pathways. C2C12 myotubes were incubated with resveratrol in the presence of increasing concentrations of glucose, and metabolic and clock proteins were measured for 24 h. Resveratrol led to SIRT1, AMPK and PP2A activation. Myotubes treated with increasing glucose concentrations showed higher activation of the mTOR signaling pathway. However, resveratrol did not activate the mTOR signaling pathway, except for P70S6K and S6. In accordance with the reduced mTOR activity, resveratrol led to advanced circadian rhythms and reduced levels of pBMAL1 and CRY1. Resveratrol increased myogenin expression and advanced its rhythms. In conclusion, resveratrol activates the SIRT1-AMPK-PP2A axis, advances circadian rhythms and induces muscle development.
... NFTs and paired helical filaments are formed due to tau hyperphosphorylation, which impairs cytoskeletal and associated transport systems, alters cellular signaling, and causes mitochondrial dysfunction [167][168][169]. Tau hyperphosphorylation and subsequent NFT formation can be [170]. Furthermore, resveratrol has potential to inhibit tau hyperphosphorylation. ...
Alzheimer’s disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aβ biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.
... Resveratrol further inhibits the phosphoinositide-3 kinase (PI3K)/AKT pathway and promotes neuronal survival [103]. It also stimulates PP2A activation and promotes tau dephosphorylation [104]. ...
Alzheimer’s disease’s pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD rendering it a major target for therapeutic development. Reactive oxygen species (ROS) generated by altered mitochondrial function, dysregulated electron transport chain and other sources elevate aggregated Aβ and neurofibrillary tangles which further stimulating the production of ROS. Oxidative stress induced damage to lipids, proteins and DNA result in neuronal death which leads to AD. In addition, oxidative stress induces apoptosis that is triggered by the modulation of ERK1/2 and Nrf2 pathway followed by increased GSK-3β expression and decreased PP2A activity. Oxidative stress exaggerates disease condition by interfering with various signaling pathways like RCAN1, CREB/ERK, Nrf2, PP2A, NFκB and PI3K/Akt. Studies have reported the role of TNF-α in oxidative stress stimulation that has been regulated by drugs like etanercept increasing the level of anti-oxidants. Other drugs like pramipexole, memantine, carvedilol, and melatonin have been reported to activate CREB/RCAN1 and Nrf2 pathways. In line with this, epigallocatechin gallate and genistein also target Nrf2 and CREB pathway leading to activation of downstream pathways like ARE and Keap1 which ameliorate oxidative stress condition. Donepezil and resveratrol reduce oxidative stress and activate AMPK pathway along with PP2A activation thus promoting tau dephosphorylation and neuronal survival. This study describes in detail the role of oxidative stress in AD, major signaling pathways involving oxidative stress induced AD and drugs under development targeting these pathways which may aid in therapeutic advances for AD.
Graphical abstract
... Resveratrol exhibits strong anti-inflammatory properties. This has been fully confirmed by numerous biological experiments in vivo and in vitro [87][88][89][90] . ...
... 81 Resveratrol increases PP2A activity by preventing its degradation through diminished expression of MID1 ubiquitin. 83 NDP52 and p62 are the two major proteins involved in autophagy and their expression is increased by EGCG, thus promoting clearance of hyperphosphorylated tau protein. 84 Another major target in AD is the telomere length which actually shortens with aging and telomere malfunction is linked with the pathogenesis of AD. 28 Vitamin A and vitamin C increase telomere length via several mechanisms including DNA repair and methylation, and by regulating the function of telomerase enzyme, which adds repeating telomere units to the chromosome ends as shown in Table 1. ...
Aging, a fundamental physiological process influenced by innumerable biological and genetic pathways, is an important driving factor for several aging-associated disorders like diabetes mellitus, osteoporosis, cancer, and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. In the modern era, the several mechanisms associated with aging have been deeply studied. Treatment and therapeutics for age-related diseases have also made considerable advances; however, for the effective and long-lasting treatment, nutritional therapy particularly including dietary polyphenols from the natural origin are endorsed. These dietary polyphenols (e.g., apigenin, baicalin, curcumin, epigallocatechin gallate, kaempferol, quercetin, resveratrol, and theaflavin), and many other phytochemicals target certain molecular, genetic mechanisms. The most common pathways of age-associated diseases are mitogen-activated protein kinase, reactive oxygen species production, nuclear factor kappa light chain enhancer of activated B cells signaling pathways, metal chelation, c-Jun N-terminal kinase, and inflammation. Polyphenols slow down the course of aging and help in combatting age-linked disorders. This exemplified in the form of clinical trials on specific dietary polyphenols in various aging-associated diseases. With this context in mind, this review reveals the new insights to slow down the aging process, and consequently reduce some classic diseases associated with age such as aforementioned, and targeting age-associated diseases by the activities of dietary polyphenols of natural origin.
... The loss of its function results in increased PP2A protein levels and activity [163]. Both in vitro and in vivo, RES treatment destabilized the ubiquitin ligase MID1 and its mRNA, which directly interfered with the MID1-α4-PP2A degradation complex by decreasing MID1 protein expression, leading to an increase in microtubule-associated PP2A activity and the time-and dose-dependent dephosphorylation of tau [164]. Similarly, in the brain of CdCl2-treated rats, trans-resveratrol inhibited tau phosphorylation by activating PP2A and inhibiting GSK3β activity. ...
Protein aggregation is one of the hallmarks of aging and aging-related diseases, especially for the neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and others. In these diseases, many pathogenic proteins, such as amyloid-β, tau, α-Syn, Htt, and FUS, form aggregates that disrupt the normal physiological function of cells and lead to associated neuronal lesions. Protein aggregates in NDs are widely recognized as one of the important targets for the treatment of these diseases. Natural products, with their diverse biological activities and rich medical history, represent a great treasure trove for the development of therapeutic strategies to combat disease. A number of in vitro and in vivo studies have shown that natural products, by virtue of their complex molecular scaffolds that specifically bind to pathogenic proteins and their aggregates, can inhibit the formation of aggregates, disrupt the structure of aggregates and destabilize them, thereby alleviating conditions associated with NDs. Here, we systematically reviewed studies using natural products to improve disease-related symptoms by reducing or inhibiting the formation of five pathogenic protein aggregates associated with NDs. This information should provide valuable insights into new directions and ideas for the treatment of neurodegenerative diseases.
... MID1, by reducing the activity of PP2A, can indirectly increase BACE1 translation and Tau phosphorylation. It was shown that the disassembly of the MID1-PP2A complex by specific drugs may target both pathological hallmarks of AD (Hettich et al., 2014;Schweiger et al., 2017). Second, the protein synthesis of APP is controlled by MID1 through the modulation of mTOR-eIF signaling . ...
Ubiquitination is a post-translation modification process crucial to control protein degradation, localization, and activity. Tripartite Motif (TRIM) proteins participate in the ubiquitination process behaving as E3 ubiquitin ligases, responsible for the specific recognition of the substrate to be ubiquitinated. In the opposite process, Deubiquitinating enzymes (DUBs) can deconjugate the ubiquitin from the protein target. The antagonism of DUBs and E3s is essential to maintain protein homeostasis and signaling in cells.
In this project, we focused on TRIM18 (also named MID1) which when mutated causes the X-linked form of Opitz G/BBB Syndrome (XLOS). MID1 controls the ubiquitin-mediated proteasomal degradation of the catalytic subunit of PP2A (PP2AC), one of the major phosphatases in the cell. Although MID1 mutations lead to an increase in PP2AC levels, the exact mechanism remains unclear. The main objective of this project was to find DUBs that work in conjunction with MID1 rescuing the increase of PP2AC level observed upon its mutations.
We specifically silenced 24 DUBs and analyzed the protein abundance of PP2AC. A decrease in the protein target levels will be indicative of a suitable DUB candidate to further study. We also made the opposite assay, overexpressing the same 24 DUBs, in this case, the DUBs overexpression should increase the PP2AC protein. From both screenings, we found USP8 as a good candidate, which we confirmed in further assays, to modulate the PP2AC levels.
Consistently with the regulation of PP2AC, USP8 overexpression alters 4E-BP1
phosphorylation levels, affecting the mTOR pathway. To conclude USP8/MID1 is a functional pair controlling the degradative fate of PP2AC.
Furthermore, we noticed that in Mouse Embryo Fibroblasts from Mid1 KO, the Usp8 protein levels were up regulated. We found that USP8 levels are decreased in both the cytoplasmic and nuclear fractions when MID1 was overexpressed, recovering the USP8 levels when using the ΔRING form of MID1 (the non-catalytic form). Moreover, the nuclear fraction of PP2AC decreased when MID1 was overexpressed and increased when USP8 was overexpressed.
To conclude we discovered a new DUB/TRIM pair that works in a highly coordinated manner. MID1 controls the levels of USP8 in the cytoplasm and nucleus, and both MID1/USP8 control the levels of PP2AC, a mutual substrate, in the nucleus fraction. These findings will be relevant in basic knowledge and for the future investigation of potential therapeutic.
... The P-Tau injuries affect glial action, which leads to adverse outcomes for glial cells, astrocytes, and non-cell autonomous results on the safety and structure of neurons [98]. Schweiger et al. represented that RES as an antioxidant compound diminishes phosphorylation of P-Tau and causes improved behaviour and cognitive disorder in vitro and in vivo [99]. It has been reported that RES can inhibit tauopathy by reducing P-Tau in a mouse AD model [51]. ...
Alzheimer's disease (AD) is one of the chief neurological difficulties in the aged population, identified through dementia, memory disturbance, and reduced cognitive abilities. β-amyloid (Aβ) plaques aggregations, generation of reactive oxygen species, and mitochondrial dysfunction are among the major signs of AD. Regarding the urgent need for the development of novel treatments for neurodegenerative diseases, researchers have recently perused the function of natural phytobioactive combinations, such as resveratrol (RES), in vivo and in vitro (animal models of AD). Investigations have shown the neuroprotective action of RES. This compound can be encapsulated by several methods (e.g. polymeric nanoparticles (NPs), solid lipid nanoparticles, Micelles, and liposomes). This antioxidant compound, however, barely crosses the blood-brain barrier (BBB), thereby limiting its bioavailability and stability at the target sites in the brain. Thanks to nanotechnology, the efficiency of AD therapy can be improved by encapsulating the drugs in a NP with a controlled size (1-100 nm). This article addressed the use of RES, as a Phytobioactive compound, to decrease the oxidative stress. Encapsulation of this compound in the form of nanocarriers to treat neurological diseases to improve BBB crossing is also discussed.
... The antioxidant properties and/or potent free-radical scavenging activity of resveratrol have been reported in several in vitro and in vivo studies, which demonstrated that chronic resveratrol treatment reduced the production of malondialdehyde and nitrite and restored glutathione and protect against neuronal damage in AD (Gomes et al., 2018;Sadi and Konat, 2016;Wang et al., 2018). Additionally, resveratrol not only plays a role in the protection against ROS, but it can also modulate important glial functions, including glutamate uptake activity, GSH, improved functional recovery, and decreased DNA fragmentation and apoptosis (Lu et al., 2013;Schweiger et al., 2017). Thus, there are enough evidence indicating that these antioxidative compounds could be useful for development of effective therapeutics for AD treatment in future. ...
Oxidative stress has been established as a well-known pathological condition in several neurovascular diseases. It starts with increased production of highly oxidizing free-radicals (e.g. reactive oxygen species; ROS and reactive nitrogen species; RNS) and becomes too high for the endogenous antioxidant system to neutralize them, which results in a significantly disturbed balance between free-radicals and antioxidants levels and causes cellular damage. A number of studies have evidently shown that oxidative stress plays a critical role in activating multiple cell signaling pathways implicated in both progression as well as initiation of neurological diseases. Therefore, oxidative stress continues to remain a key therapeutic target for neurological diseases. This review discusses the mechanisms involved in reactive oxygen species (ROS) generation in the brain, oxidative stress, and pathogenesis of neurological disorders such as stroke and Alzheimer's disease (AD) and the scope of antioxidant therapies for these disorders.
... Resveratrol has been shown to inhibit the hyperphosphorylation of Tau (He et al., 2016); additionally, in the senescence accelerated mice P8 (SAMP8), resveratrol inhibits Ser 396 Tau phosphorylation by GSK-3β (Porquet et al., 2013). Resveratrol can also modulate Tau hyperphosphorylation by increasing PP2A activity, which leads to Tau dephosphorylation (Schweiger et al., 2017). Similarly, in an okaidic acid-injection model for AD, curcumin treatment inhibited Tau hyperphosphorylation through activation of GSK-3β pathway (Wang et al., 2019). ...
Alzheimer′s disease (AD) is an irreversible progressive neurodegenerative disease affecting approximately 50 million people worldwide. It is estimated to reach 152 million by the year 2050. AD is the fifth leading cause of death among Americans age 65 and older. In spite of the significant burden the disease imposes upon patients, their families, our society, and our healthcare system, there is currently no cure for AD. The existing approved therapies only temporarily alleviate some of the disease’s symptoms, but are unable to modulate the onset and/or progression of the disease. Our failure in developing a cure for AD is attributable, in part, to the multifactorial complexity underlying AD pathophysiology. Nonetheless, the lack of successful pharmacological approaches has led to the consideration of alternative strategies that may help delay the onset and progression of AD. There is increasing recognition that certain dietary and nutrition factors may play important roles in protecting against select key AD pathologies. Consistent with this, select nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory, and neurotrophic properties and as such, could serve as lead candidates for further novel AD therapeutic developments. Here we summarize some of the more promising dietary phytochemicals, particularly polyphenols that have been shown to positively modulate some of the important AD pathogenesis aspects, such as reducing β-amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation, and synapse loss. We also discuss the recent development of potential contribution of gut microbiome in dietary polyphenol function.
