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Tau protein regulates, maintains and stabilizes microtubule assembly under normal physiological conditions. In certain pathological circumstances, tau is post-translationally modified predominantly via phosphorylation and glycosylation. Hyper-phosphorylation of tau in Alzheimer's disease (AD) resulted in aggregated neurofibrillary tangles (NFTs) formation. Unfortunately, absence of tau 3D structure makes difficult to understand exact mechanism involved in tau pathology. Here by using ab-initio modelling, we predicted a tau 3D structure that not only explains its binding with microtubules but also elucidates NFTs formation. O -linked β- N -acetylglucosaminylation (O -β-GlcNAc) is thought to regulate tau phosphorylation on single or proximal Ser/Thr residues (called as Yin-Yang sites). In this study, we not only validate the previously described three-serine residues (208, 238 and 400) as Yin-Yang sites but also predicted 22 more possible Ser/Thr O- glycosylation sites. Among them seventeen residues were predicted as possible Yin-Yang sites and are proposed to mediate NFT formation in AD. These predicted Yin-Yang sites may act as attractive therapeutic targets for the drug development in AD. Predicted 3D structure of tau 441 was highly accessible for phosphorylation and hyperphosphorylation, and showed higher surface accessibility for interplay between O -β-GlcNAc and phosphorylation modifications. Kinases and phosphatases involved in tau phosphorylation are conserved in human and other organisms. Homology modelling revealed conserved catalytic domain for both human and C. elegans O -GlcNAc transferase (OGT), suggesting that transgenic C. elegans expressing human tau may be a suitable model system to study these modifications. • Phosphorylation can be inhibited by addition of O-β-GlcNAc (known as Yin-Yang sites phenomenon. • 3D structure of tau remains mystery that resulted in poor understanding of disease pathology. • Our predicted 3D structure of tau is being capable of phosphorylated, hyperphosphorylated and O- glycosylated. • Our proposed 17 yin-yang residues can act as possible therapeutic targets in AD pathogenesis. • C. elegans model system can be used to assess these interactions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related disease characterized by loss of memory and disrupted thinking that is associated with altered energy metabolism. Variants of an important enzyme of energy metabolism, dihydrolipoamide dehydrogenase ( dld) , have been genetically linked to late-onset AD. Moreover, reduced activity of DLD-containing enzyme complexes is associated with AD progression. To understand how energy metabolism influences AD progression, we exposed C. elegans expressing human Aβ peptide to the chemical inhibitor of DLD, 2-methoxyindole-5-carboxylic acid (MICA). Expression of human Aβ in C. elegans causes a variety of pathologies that can be used to monitor the efficacy of treatments against proteotixicity. We found that MICA alleviated the Aβ-induced paralysis and improved cholinergic neurotransmission in C. elegans that express Aβ in muscle cells. MICA also reduced both hypersensitivity to serotonin and perturbation of chemotaxis associated with neuronal expression of human Aβ. Furthermore, low doses of MICA helped to alleviate an Aβ-mediated decrease in fecundity. Protection against AD pathogenesis by MICA in the C. elegans model was associated with a decrease in Aβ oligomerization that could be reversed by the calcium ionophore, A23187. MICA also caused a decrease in oxidative stress, which could also contribute to the protective effect of MICA against Aβ toxicity. [ABSTRACT FROM AUTHOR]

Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer's disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM. [ABSTRACT FROM AUTHOR]

Amyloid beta (Aβ) plaques formation and impaired neurotransmission and neuronal behaviors are primary hallmarks of Alzheimer's disease (AD) that are further associated with impaired glucose metabolism in elderly AD's patients. However, the exact role of glucose metabolism on disease progression has not been elucidated yet. In this study, the effect of glucose on Aβ-mediated toxicity, neurotransmission and neuronal behaviors has been investigated using a C. elegans model system expressing human Aβ. In addition to regular diet, worms expressing Aβ were supplemented with different concentrations of glucose and glycerol and 5 mM 2-deoxyglucose to draw any conclusions. Addition of glucose to the growth medium delayed Aβ-associated paralysis, promoted abnormal body shapes and movement, unable to restore impaired acetylcholine neurotransmission, inhibited egg laying and hatching in pre-existing Aβ-mediated pathology. The harmful effects of glucose may associate with an increase in toxic Aβ oligomers and impaired neurotransmission. O-β-GlcNAcylation (O-GlcNAc), a well-known post-translational modification is directly associated with glucose metabolism and has been found to ameliorates the Aβ- toxicity. We reasoned that glucose addition might induce O-GlcNAc, thereby protect against Aβ. Contrary to our expectations, induced glucose levels were not protective. Increasing O-GlcNAc, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and, therefore, reduce Aβ- toxicity but not in the presence of high glucose. The effects of glucose cannot be effectively managed by manipulating O-GlcNAc in AD models of C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression. [ABSTRACT FROM AUTHOR]

Impaired insulin signaling has been thought of as important step in both Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates (IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs. Two important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine (Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and promoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTMand inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more than 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM. [ABSTRACT FROM AUTHOR]