The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global ...perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.
Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ identification and quantification p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative ADNI, N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease EASE-AD). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio HR = 4.430, 95% confidence interval CI = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.
We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how ...perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.
We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD ASY: n = 13; Control CN: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus ITG and middle frontal gyrus MFG), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione GSH: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.
In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
► 2mM Oleic acid induced hepatic steatosis in HepG2 cells. ► Quercetin ameliorates insulin resistance which is major indication during NAFLD. ► Fat accumulation was decreased and cell proliferation ...was increased by quercetin. ► Quercetin inhibit IL-8 and TNF-alpha with increased cellular glutathione. ► First evidence regarding pharmacological action of quercetin to overcome NAFLD.
Hepatic lipid accumulation and oxidative stress contribute to non-alcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activity of quercetin would attenuate events leading to NAFLD. Addition of 2.0mM oleic acid (OA) into the culture media induced fatty liver condition in HepG2 cells by 24h. It was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. The inflammatory cytokines TNF-α and IL-8 levels were significantly increased with decreased antioxidant molecules. OA induced insulin resistance which was evident by inhibition of glucose uptake and cell proliferation. Quercetin (10μM) increased cell proliferation by 3.05 folds with decreased TAG content (45%) and was effective in increasing insulin mediated glucose uptake by 2.65 folds. The intracellular glutathione content was increased by 2.0 folds without substantial increase in GSSG content. Quercetin (10μM) decreased TNF-α and IL-8 by 59.74% and 41.11% respectively and inhibited generation of lipid peroxides by 50.5%. In addition, RT-PCR results confirmed quercetin (10μM) inhibited TNF-alpha gene expression. Further, superoxide dismutase, catalase and glutathione peroxidase activities were increased by 1.68, 2.19 and 1.71 folds respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by quercetin. Hence, quercetin effectively reversed NAFLD symptoms by decreased triacyl glycerol accumulation, insulin resistance, inflammatory cytokine secretion and increased cellular antioxidants in OA induced hepatic steatosis in HepG2 cells.
It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis.
Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we ...measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose.
Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations.
Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.
•Brain tissue glucose is associated with severity of Alzheimer's disease (AD) pathology and symptom onset.•Reduced brain glycolytic flux is associated with severity of AD pathology and symptom onset.•Neuronal glucose transporter-3 is lower in AD.•Lower glucose transporter-3 levels are associated with more severe AD pathology.•Increase in plasma glucose decades before death is related to higher brain glucose.
Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that ...inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.
► Developed a new approach for nanoparticle synthesis by green tea extract with enhancement of stability/longevity. ► In-situ, green synthesis of about 30
nm metal nanoparticles in functionalized ...microfiltration membranes for degradation of pollutants. ► Successfully demonstrated a membrane-based approach for the reductive degradation of toxic trichloroethylene from water.
Membranes containing reactive nanoparticles (Fe and Fe/Pd) immobilized in a polymer film (polyacrylic acid, PAA-coated polyvinylidene fluoride, PVDF membrane) are prepared by a new method. In the present work a biodegradable, non-toxic-“green” reducing agent, green tea extract was used for nanoparticle (NP) synthesis, instead of the well-known sodium borohydride. Green tea extract contains a number of polyphenols that can act as both chelating/reducing and capping agents for the nanoparticles. Therefore, the particles are protected from oxidation and aggregation, which increases their stability and longevity. The membrane supported NPs were successfully used for the degradation of a common and highly important pollutant, trichloroethylene (TCE). The rate of TCE degradation was found to increase linearly with the amount of Fe immobilized on the membrane, the surface normalized rate constant (
k
SA) being 0.005
L/m
2
h. The addition of a second catalytic metal, Pd, to form bimetallic Fe/Pd increased the
k
SA value to 0.008
L/m
2
h. For comparison purposes, Fe and Fe/Pd nanoparticles were synthesized in membranes using sodium borohydride as a reducing agent. Although the initial
k
SA values for this case (for Fe) are one order of magnitude higher than the tea extract synthesized NPs, the rapid oxidation reduced their reactivity to less than 20% within 4 cycles. For the green tea extract NPs, the initial reactivity in the membrane domain was preserved even after 3 months of repeated use. The reactivity of TCE was verified with “real” water system.
An efficient, green and reliable method for the direct reductive amination of aldehydes was developed using an environmentally benign bentonite‐gold nanohybrid catalyst. Use of this heterogeneous ...catalyst affords a variety of secondary amines in excellent yield under ambient reaction conditions in the presence of phenyldimethylsilane as mild hydride donor. The catalyst is recyclable, selective and is well applicable for the gram‐scale preparation of secondary amines.
The arbuscular mycorrhizal (AM) symbiosis is a mutualistic endosymbiosis formed by plant roots and AM fungi. Most vascular flowering plants have the ability to form these associations, which have a ...significant impact on plant health and consequently on ecosystem function. Nutrient exchange is a central feature of the AM symbiosis, and AM fungi obtain carbon from their plant host while assisting the plant with the acquisition of phosphorus (as phosphate) from the soil. In the AM symbiosis, the fungus delivers Pi to the root through specialized hyphae called arbuscules. The molecular mechanisms of Pi and carbon transfer in the symbiosis are largely unknown, as are the mechanisms by which the plant regulates the symbiosis in response to its nutrient status. Plants possess many classes of Pi transport proteins, including a unique clade (Pht1, subfamily I), members of which are expressed only in the AM symbiosis. Here, we show that MtPT4, a Medicago truncatula member of subfamily I, is essential for the acquisition of Pi delivered by the AM fungus. However, more significantly, MtPT4 function is critical for AM symbiosis. Loss of MtPT4 function leads to premature death of the arbuscules; the fungus is unable to proliferate within the root, and symbiosis is terminated. Thus, Pi transport is not only a benefit for the plant but is also a requirement for the AM symbiosis.
The genetic diversity of our crop plants has been substantially reduced during the process of domestication and breeding. This reduction in diversity necessarily constrains our ability to expand a ...crop’s range of cultivation into environments that are more extreme than those in which it was domesticated, including into “sustainable” agricultural systems with reduced inputs of pesticides, water, and fertilizers. Conversely, the wild progenitors of crop plants typically possess high levels of genetic diversity, which underlie an expanded (relative to domesticates) range of adaptive traits that may be of agricultural relevance, including resistance to pests and pathogens, tolerance to abiotic extremes, and reduced dependence on inputs. Despite their clear potential for crop improvement, wild relatives have rarely been used systematically for crop improvement, and in no cases, have full sets of wild diversity been introgressed into a crop. Instead, most breeding efforts have focused on specific traits and dealt with wild species in a limited and typically ad hoc manner. Although expedient, this approach misses the opportunity to test a large suite of traits and deploy the full potential of crop wild relatives in breeding for the looming challenges of the 21st century. Here we review examples of hybridization in several species, both intentionally produced and naturally occurring, to illustrate the gains that are possible. We start with naturally occurring hybrids, and then examine a range of examples of hybridization in agricultural settings.
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