Biology subjects

Ahmad, W.

Publications and source records attributed to Ahmad, W..

4 recordsLinked to original sources

bioRxiv2017

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

Declines in energy metabolism and associated mitochondrial enzymes are linked to the progression of Alzheimers disease (AD). Dihydrolipoamide dehydrogenase (dld) and two of its enzyme complexes namely, pyruvate dehydrogenase and -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 A{beta} peptide. dld-1 gene suppression improved many aspects of vitality and function directly affected by A{beta} 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 A{beta} peptide, but does reduce the formation of toxic A{beta} oligomers. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) acts synergistically with A{beta} to overcome the protective effect of dld-1 gene suppression. Another metabolic toxin, phosphine, acted additively with A{beta}. Our work supports the hypothesis that lowering energy metabolism may protect against A{beta} pathogenicity, but that this may increase susceptibility to other metabolic disturbances.

neuroscience↗

bioRxiv2017

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

Formation of A{beta} plaques from peptide oligomers and development of neurofibrillary tangles from hyperphosphorylated tau are hallmarks of Alzheimers 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 A{beta} 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 A{beta}-associated paralysis, though it was unable to restore previously impaired acetylcholine neurotransmission in pre-existing A{beta}-mediated pathology. Glucose also inhibited egg laying and hatching in the worms that express A{beta}. The harmful effects of glucose were associated with an increase in toxic A{beta} oligomers. Increased phosphorylation of tau is associated with formation of neurofibrillary tangles (NFTs) and increased severity of AD, but O-{beta}-GlcNAcylation can inhibit phosphorylation of adjacent phosphorylation sites. We reasoned that high glucose levels might induce tau O-{beta}-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectation, glucose increased tau phosphorylation but not O-{beta}-GlcNAcylation. Increasing O-{beta}-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-{beta}-GlcNAcylation by suppressing O-GlcNAc transferase (ogt-1) gene causes an increase in tau phosphorylation. These results suggest that protective O-{beta}-GlcNAcylation is not induced by glucose. Instead, as with vertebrates, we demonstrate that high levels of glucose exacerbate disease progression by promoting A{beta} aggregation and tau hyperphosphorylation, resulting in disease symptoms of increased severity. The effects of glucose cannot be effectively managed by manipulating O-{beta}-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.

neuroscience↗

bioRxiv2017

Effect of dihydrolipoamide dehydrogenase (dld-1) on human tau phosphorylation in a C. elegans model of Alzheimer’s Disease

The microtubule associated tau protein becomes hyperphosphorylated in Alzheimers disease (AD). While tau 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 suppression or inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) either by RNAi or 2-methoxyindole-2-carboxylic acid (MICA) respectively, resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical inhibition 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.

neuroscience↗

bioRxiv2017

Acute and chronic toxicity assessment of benzylpenicillin G residue in cooked meat

The current level of penicillin use and its persisting residues in livestock is potentially concerning; the toxicity of penicillin residues in heat-treated animal food products (HAFP) is yet to be elucidated. In this study, the acute and chronic toxicity of benzylpenicillin G (BPG) residues in HAFP was investigated in a mouse model. The calculated LD50 of BPG heated to cooking temperature (BPHCT) was 933.04 mg kg-1 [b.w.] intraperitoneally corresponding to 3.75 times lower than its prototype. Mice fed on the experimental diet containing heat-treated beef with high BPG levels for 6 months displayed a reduction in body weight and altered serum values indicating for liver and renal function. Further, the organ ratios of intestinal and spleen were increased. Histopathological changes were observed in the liver, lung and parenchyma testis tissue. BPHCT residue induced sperm aberration and micronucleated polychromatic erythrocytes formation. Present results indicate that prolonged exposure of BPHCT at higher levels of residue might have an impact on public health. Importantly the toxic concentrations of BPHCT are relatively high compared with levels that would result from the degradation of antibiotic residues in meat from animals that have received a therapeutic dose of BPG.

pharmacology and toxicology↗