scholarly journals Dihydrolipoamide dehydrogenase suppression induce human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Metabolism ◽  
Tau Protein ◽  
Tau Phosphorylation ◽  
Whole Body ◽  
Ionophore A23187 ◽  
Dihydrolipoamide Dehydrogenase ◽  
C Elegans ◽  
Glucose Levels

AbstractThe microtubule associated tau protein becomes hyperphosphorylated in Alzheimer’s disease (AD). While hyperphosphorylation promotes neurodegeneration, the cause and consequences of this abnormal modification are poorly understood. As impaired energy metabolism is an important hallmark of AD progression, we tested whether it could trigger phosphorylation of human tau protein in a transgenic C. elegans model of AD. We found that inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Hyperglycemia and tau phosphorylation were induced by either epigenetic suppression of the dld-1 gene or by inhibition of the DLD enzyme by the inhibitor, 2-methoxyindole-2-carboxylic acid (MICA). Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical or genetic suppression of DLD, it was unable to reduce tau phosphorylation induced by hyperglycemia. While inhibition of the dld-1 gene or treatment with MICA partially reversed the inhibition of acetylcholine neurotransmission by tau, neither treatment affected tau inhibited mobility. Conclusively, any abnormalities in energy metabolism were found to significantly affect the AD disease pathology.

scholarly journals Suppression of the dihydrolipoamide dehydrogenase gene (dld-1) protects against the toxicity of human amyloid beta in C. elegans model of Alzheimer’s disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Energy Metabolism ◽  
Mitochondrial Enzymes ◽  
Aβ Peptide ◽  
Dihydrolipoamide Dehydrogenase ◽  
Gene Suppression ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease ◽  
Enzyme Complexes

AbstractDeclines in energy metabolism and associated mitochondrial enzymes are linked to the progression of Alzheimer’s disease (AD). Dihydrolipoamide dehydrogenase (dld) and two of its enzyme complexes namely, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase are associated with AD and have a significant role in energy metabolism. Interestingly, dld gene variants are genetically linked to late-onset AD; and reduced activity of DLD-containing enzyme complexes has been observed in AD patients. To understand how energy metabolism influences AD progression, we suppressed the dld-1 gene in C. elegans expressing the human Aβ peptide. dld-1 gene suppression improved many aspects of vitality and function directly affected by Aβ pathology in C. elegans. This includes protection against paralysis, improved fecundity and improved egg hatching rates. Suppression of the dld-1 gene restores normal sensitivity to aldicarb, levamisole and serotonin, and improves chemotaxis. Suppression of dld-1 does not decrease levels of the Aβ peptide, but does reduce the formation of toxic Aβ oligomers. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) acts synergistically with Aβ to overcome the protective effect of dld-1 gene suppression. Another metabolic toxin, phosphine, acted additively with Aβ. Our work supports the hypothesis that lowering energy metabolism may protect against Aβ pathogenicity, but that this may increase susceptibility to other metabolic disturbances.

scholarly journals Tau aggregates possibly compromise neuronal health in the C. elegans model of Alzheimer’s disease

2020 ◽  
Vol 1 (6) ◽  
pp. 46-48
Author(s):  
Sanjib Guha ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Intercellular Space ◽  
Senile Plaques ◽  
Aβ Peptide ◽  
Progressive Decline ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common degenerative brain disease in the aged population [1]. By 2050, AD prevalence is expected to increase from 4.7 million (based on 2010 census) to 13.8 million people [2]. It is characterized by the progressive decline of cognition and memory, as well as changes in behavior and personality [1]. Pathological hallmarks of AD include mainly formation of senile plaques consisting of amyloid-beta (Aβ) peptide in the intercellular space and neurofibrillary tangles (NFTs) in the cell bodies, which are primarily composed of abnormally modified tau protein [3].

scholarly journals Glucose facilitates Aβ oligomerization and tau phosphorylation in C. elegans model of Alzheimer’s disease

2017 ◽  
Author(s):  
Waqar Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Disease Progression ◽  
Neurofibrillary Tangles ◽  
Tau Phosphorylation ◽  
Egg Laying ◽  
Aβ Oligomers ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

AbstractFormation of Aβ plaques from peptide oligomers and development of neurofibrillary tangles from hyperphosphorylated tau are hallmarks of Alzheimer’s disease (AD). These markers of AD severity are further associated with impaired glucose metabolism. However, the exact role of glucose metabolism on disease progression has not been elucidated. In this study, the effects of glucose on Aβ and tau-mediated toxicity are investigated using a C. elegans model system. We find that addition of glucose or 2-deoxy-d-glucose (2DOG) to the growth medium delayed Aβ-associated paralysis, though it was unable to restore previously impaired acetylcholine neurotransmission in pre-existing Aβ-mediated pathology. Glucose also inhibited egg laying and hatching in the worms that express Aβ. The harmful effects of glucose were associated with an increase in toxic Aβ oligomers. Increased phosphorylation of tau is associated with formation of neurofibrillary tangles (NFTs) and increased severity of AD, but O-β-GlcNAcylation can inhibit phosphorylation of adjacent phosphorylation sites. We reasoned that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectation, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and therefore reduce tau phosphorylation. Furthermore, reducing O-β-GlcNAcylation by suppressing O-GlcNAc transferase (ogt-1) gene causes an increase in tau phosphorylation. These results suggest that protective O-β-GlcNAcylation is not induced by glucose. Instead, as with vertebrates, we demonstrate that high levels of glucose exacerbate disease progression by promoting Aβ aggregation and tau hyperphosphorylation, resulting in disease symptoms of increased severity. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in the tau models of AD in C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

scholarly journals Root-Securing and Brain-Fortifying Liquid Upregulates Caveolin-1 in Cell Model with Alzheimer’s Disease through Inhibiting Tau Phosphorylation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Depei Yuan ◽  
Chuhua Zeng ◽  
Qianfeng Chen ◽  
Fengjie Wang ◽  
Lin Yuan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Hippocampal Neurons ◽  
Cell Model ◽  
Tau Phosphorylation ◽  
Caveolin 1 ◽  
Sd Rats ◽  
A Cell ◽  
Underlying Mechanisms

In order to explore the effect of root-securing and brain-fortifying Liquid- (RSBFL-) mediated caveolin-1 (CAV-1) on phosphorylation of Tau protein and to uncover underlying mechanisms of RSBFL for the prevention and treatment of Alzheimer’s disease (AD), hippocampal neurons isolated from neonatal SD rats and cultured in DMEM-F12 medium were induced by exogenous Aβ1–42 to establish a cell model with AD. Meanwhile, pEGFP-C1-CAV1 and CAV1-shRNA plasmids were transfected into hippocampal neurons for CAV-1 overexpression and silence, respectively. The serum containing RSBFL was prepared for the intervention of AD model cells. The expression of CAV-1, GSK-3β, and p-Tau in normal hippocampal neurons and AD model cells in the presence of serum containing RSBFL was evaluated. The model hippocampal neurons with AD induced by Aβ1–42 revealed an obvious CAV-1 inhibition, enhanced GSK-3βactivity, and abnormal Tau phosphorylation. In contrast, the treatment with serum containing RSBFL could upregulate CAV-1 in AD hippocampal neurons (P<0.05) with improved p-GSK-3βSer9and reduced p-GSK-3βTyr216(P<0.01), as well as suppressed abnormal phosphorylation of Tau protein. Therefore, RSBFL has an excellent protective effect on hippocampal neurons through increasing CAV-1 expression, inhibiting GSK-3βactivity, and reducing excessive abnormal phosphorylation of Tau protein.

scholarly journals Cross-species metabolomic analysis of DDT and Alzheimer's disease-associated tau toxicity

2021 ◽  
Author(s):  
Vrinda Kalia ◽  
Megan M Niedzwiecki ◽  
Joshua M Bradner ◽  
Fion K Lau ◽  
Meghan L Bucher ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Population Study ◽  
Mitochondrial Function ◽  
Tau Protein ◽  
Human Population ◽  
Environmental Toxicants ◽  
C Elegans ◽  
Increased Risk

Background. The formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimer's disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with an increased risk of AD. Objectives. To determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. Methods. In the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. Results. Plasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. Conclusion. The model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

scholarly journals Potential of medicinal plant compounds to targeting Tau protein in the therapy of Alzheimer’s disease– A review

Biomedicine ◽  
2020 ◽  
Vol 39 (2) ◽  
pp. 217-227
Author(s):  
Ella Fils Armand ◽  
Manjula Shantaram ◽  
Njayou Frédéric Nico ◽  
Fewou Ngamli Simon ◽  
Moundipa Fewou Paul
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medicinal Plant ◽  
Amyloid Beta ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Tau Phosphorylation ◽  
Amyloid Beta Peptides ◽  
Diverse Range ◽  
Beta Peptides

Alzheimer’s disease (AD) is a devastative neurodegenerative disorder with complex etiology. AD is characterized by blood-brain barrier disruption, oxidative stress, mitochondrial impairment, neuro- inflammation, hypo-metabolism; it decreases in acetylcholine levels and a reduction of cerebral blood flow. It is also not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid- beta peptides but hyper phosphorylated Tau (tubulin binding protein) which formed senile plaque and intracellular neurofibrillary tangles respectively. However, despite the long-term and worldwide effort for a more effective therapy, the only available treatment is a symptomatic use of acetylcholinesterase inhibitors and memantine. Then, many researchers focused their attention to modulate amyloid-beta peptides. These therapeutic approaches as well as those based on cholinergic or amyloid theory have not brought the desired benefits yet. Thus, the main features related with the Tau pathology found in AD are Tau phosphorylation and aggregation. Based on the biochemically diverse range of pathological Tau protein, a number of approaches have been proposed to develop new potential therapeutics like inhibition of Tau phosphorylation, proteolysis and aggregation; promotion of intra- and extracellular Tau clearance and stabilization of microtubules (MTs). Medicinal plants have been used in different systems of medicine and exhibited their powerful roles in the management and cure of memory disorders. This review paper discusses the potential of medicinal plant molecules to targeting Tau protein in Alzheimer’s disease therapy.    

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