Nicotinamide adenine dinucleotide (NAD
) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative ...phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD
depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD
, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD
levels. Recent studies have shown that enhancing NAD
levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD
anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the
NAD
synthesis pathway in mammalian cells. NAD
can also be produced by the NAD
salvage pathway.
In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD
precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD
decline in degenerative disease states and physiological aging.
Results obtained in recent years have shown that NAD
precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD
synthesis
their location in the NAD
anabolic pathway. Increased synthesis of NAD
promotes protective cell responses, further demonstrating that NAD
is a regulatory molecule associated with several biochemical pathways.
In the next few years, the refinement of personalized therapy for the use of NAD
precursors and improved detection methodologies allowing the administration of specific NAD
precursors in the context of patients' NAD
levels will lead to a better understanding of the therapeutic role of NAD
precursors in human diseases.
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant ...antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD(+)-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.
Soluble amyloid-β (Aβ) oligomers have been shown to induce oxidative stress, synaptic dysfunction and memory deficits which have been reported in Alzheimer's disease (AD). Administration of ...γ-glutamylcysteine (GGC), a precursor to glutathione (GSH) can replenish depleted GSH levels, by circumventing the regulation of GSH biosynthesis and providing the limiting substrate. In this study, we examined the effect of exogenous Aβ40 oligomers on biomarkers of apoptosis and cell death, oxidative stress, and neuroinflammation, in primary adult human astrocytes. Treatment with Aβ40 oligomers significantly reduced the cell viability and apoptosis of astrocyte brain cultures and decreased oxidative modifications of DNA, lipids, and protein after 24 hours. Co-treatment with GGC at 200µM also attenuated increased the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) and led to significant increases in the levels of the total antioxidant capacity (TAC) and GSH and reduced the GSSG/GSH ratio. GGC also upregulated the level of the anti-inflammatory cytokine IL-10 and reduced the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) in Oligomeric Aβ40-treated astrocytes. Our data provides renewed insight on the beneficial effects of increased GSH levels by GGC in human astrocytes, and identifies yet another potential therapeutic strategy to attenuate the cytotoxic effects of Aβ oligomers in AD.
Introduction
Nicotinamide adenine dinucleotide (NAD
+
) is an essential pyridine nucleotide that serves as a key hydride transfer coenzyme for several oxidoreductases. It is also the substrate for ...intracellular secondary messenger signalling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase, and epigenetic regulation of gene expression by a class of histone deacetylase enzymes known as sirtuins. The measurement of NAD
+
and its related metabolites (hereafter, the NAD
+
metabolome) represents an important indicator of cellular function.
Objectives
A study was performed to develop a sensitive, selective, robust, reproducible, and rapid method for the concurrent quantitative determination of intracellular levels of the NAD
+
metabolome in glial and oocyte cell extracts using liquid chromatography coupled to mass spectrometry (LC/MS/MS).
Methods
The metabolites were separated on a versatile amino column using a dual HILIC-RP gradient with heated electrospray (HESI) tandem mass spectrometry detection in mixed polarity multiple reaction monitoring mode.
Results
Quantification of 17 metabolites in the NAD
+
metabolome in U251 human astroglioma cells could be achieved. Changes in NAD
+
metabolism in U251 cell line, and murine oocytes under different culture conditions were also investigated.
Conclusion
This method can be used as a sensitive profiling tool, tailoring chromatography for metabolites that express significant pathophysiological changes in several disease conditions and is indispensable for targeted analysis.
Tannic acid (TA) is a naturally occurring plant-derived polyphenol found in several herbaceous and woody plants, including legumes, sorghum, beans, bananas, persimmons, rasberries, wines and a broad ...selection of teas. Clinically, TA has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties. While the aetiology of Alzheimer's disease (AD) remains unclear, this complex multifactorial neurodegenerative disorder remains the most common form of dementia, and is a growing public health concern worldwide. The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of β-secretase (BACE1) activity and protein expression. BACE1 is the primary enzyme responsible for the production and deposition of Aβ peptide. TA also destabilises neurotoxic amyloid beta (Aβ) fibrils in vitro. Apart from its effects on the Aβ cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs). This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets. It also highlights the significance of TA as an important lead compound against AD.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced ...activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia.
•Meta-analysis results of cerebrospinal fluid/serum albumin quotient (Q-Alb) revealed disruption of the neurovascular unit with the ability to differentiate VCD patients from healthy ...controls.•Biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin), and neuronal injury (NfL) were found to be significantly elevated in vascular pathologies.•Measurements of tight junction proteins such as occludin and claudin-5 were upregulated in stroke and may therefore provide insights into the pathophysiology of cognitive impairment associated with vascular pathologies.•A panel of biomarkers representing multiple pathophysiological mechanisms is recommended for the diagnosis and identification of various subtypes of VCD.
The disruption of the neurovascular unit (NVU), which maintains the integrity of the blood brain barrier (BBB), has been identified as a critical mechanism in the development of cerebrovascular and neurodegenerative disorders. However, the understanding of the pathophysiological mechanisms linking NVU dysfunction to the disorders is incomplete, and reliable blood biomarkers to measure NVU dysfunction are yet to be established. This systematic review and meta-analysis aimed to identify biomarkers associated with BBB dysfunction in large vessel disease, small vessel disease (SVD) and vascular cognitive disorders (VCD).
A literature search was conducted in PubMed, EMBASE, Scopus and PsychINFO to identify blood biomarkers related to dysfunction of the NVU in disorders with vascular pathologies published until 20 November 2023. Studies that assayed one or more specific markers in human serum or plasma were included. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Effects were pooled and methodological heterogeneity examined using the random effects model.
A total of 112 studies were included in this review. Where study numbers allowed, biomarkers were analysed using random effect meta-analysis for VCD (1 biomarker; 5 studies) and cerebrovascular disorders, including stroke and SVD (9 biomarkers; 29 studies) while all remaining biomarkers (n = 17 biomarkers; 78 studies) were examined through qualitative analysis. Results of the meta-analysis revealed that cerebrospinal fluid/serum albumin quotient (Q-Alb) reliably differentiates VCD patients from healthy controls (MD = 2.77; 95 % CI = 1.97–3.57; p < 0.0001) while commonly measured biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin) and neuronal injury (NfL) were significantly elevated in vascular pathologies. A qualitative assessment of non-meta-analysed biomarkers revealed NSE, NfL, vWF, ICAM-1, VCAM-1, lipocalin-2, MMP-2 and MMP-9 levels to be upregulated in VCD, although these findings were not consistently replicated.
This review identifies several promising biomarkers of NVU dysfunction which require further validation. A panel of biomarkers representing multiple pathophysiological pathways may offer greater discriminative power in distinguishing possible disease mechanisms of VCD.
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting over 27 million people worldwide. AD represents a complex neurological disorder which is best understood as the ...consequence of a number of interconnected genetic and lifestyle variables, which culminate in multiple changes to brain structure and function. These can be observed on a gross anatomical level in brain atrophy, microscopically in extracellular amyloid plaque and neurofibrillary tangle formation, and at a functional level as alterations of metabolic activity. At a molecular level, metal dyshomeostasis is frequently observed in AD due to anomalous binding of metals such as Iron (Fe), Copper (Cu), and Zinc (Zn), or impaired regulation of redox-active metals which can induce the formation of cytotoxic reactive oxygen species and neuronal damage. Metal chelators have been administered therapeutically in transgenic mice models for AD and in clinical human AD studies, with positive outcomes. As a result, neuroimaging of metals in a variety of intact brain cells and tissues is emerging as an important tool for increasing our understanding of the role of metal dysregulation in AD. Several imaging techniques have been used to study the cerebral metallo-architecture in biological specimens to obtain spatially resolved data on chemical elements present in a sample. Hyperspectral techniques, such as particle-induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), X-ray fluorescence microscopy (XFM), synchrotron X-ray fluorescence (SXRF), secondary ion mass spectrometry (SIMS), and laser ablation inductively coupled mass spectrometry (LA-ICPMS) can reveal relative intensities and even semi-quantitative concentrations of a large set of elements with differing spatial resolution and detection sensitivities. Other mass spectrometric and spectroscopy imaging techniques such as laser ablation electrospray ionization mass spectrometry (LA ESI-MS), MALDI imaging mass spectrometry (MALDI-IMS), and Fourier transform infrared spectroscopy (FTIR) can be used to correlate changes in elemental distribution with the underlying pathology in AD brain specimens. Taken together, these techniques provide new techniques to probe the pathobiology of AD and pave the way for identifying new therapeutic targets. The current review aims to discuss the advantages and challenges of using these emerging elemental and molecular imaging techniques, and highlight clinical achievements in AD research using bioimaging techniques.
Nady Braidy1, Ross Grant1,2, Bruce J Brew3,4, Seray Adams1, Tharusha Jayasena5 and Gilles J. Guillemin1,41University of New South Wales, Faculty of Medicine, Sydney, Australia. 2Australasian Research ...Institute, Sydney Adventist Hospital, Sydney, Australia. 3St. Vincent's Centre for Applied Medical Research, Sydney, Australia. 4Department of Neurology, St. Vincent's Hospital, Sydney, Australia. 5Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia.Abstract The kynurenine pathway (KP) is a major route of L-tryptophan catabolism resulting in the production of the essential pyridine nucleotide nicotinamide adenine dinucleotide, (NAD+). Up-regulation of the KP during inflammation leads to the release of a number of biologically active metabolites into the brain. We hypothesised that while some of the extracellular KP metabolites may be beneficial for intracellular NAD+ synthesis and cell survival at physiological concentrations, they may contribute to neuronal and astroglial dysfunction and cell death at pathophysiological concentrations. In this study, we found that treatment of human primary neurons and astrocytes with 3-hydroxyanthranilic acid (3-HAA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC) at concentrations below 100 nM significantly increased intracellular NAD+ levels compared to non-treated cells. However, a dose dependent decrease in intracellular NAD+ levels and increased extracellular LDH activity was observed in human astrocytes and neurons treated with 3-HAA, 3-HK, QUIN and PIC at concentrations 100 nM and kynurenine (KYN), at concentrations above 1 μM. Intracellular NAD+ levels were unchanged in the presence of the neuroprotectant, kynurenic acid (KYNA), and a dose dependent increase in intracellular NAD+ levels was observed for TRP up to 1 mM. While anthranilic acid (AA) increased intracellular NAD+ levels at concentration below 10 μM in astrocytes. NAD+ depletion and cell death was observed in AA treated neurons at concentrations above 500 nM. Therefore, the differing responses of astrocytes and neurons to an increase in KP metabolites should be considered when assessing KP toxicity during neuroinflammation.
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