Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder amongst older adults. Features of this disease include accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles (NFT), neuroinflammation, and neurodegeneration. These result in a progressive decline in memory and executive function in patients. Anxiety-related behaviours are disparaging comorbidities of AD, but how they arise in patients remains elusive. Protein-tyrosine phosphatase 1B (PTP1B) has been associated with Aβ pathology and with anxiety in separate paradigms, but whether PTP1B is involved in anxiety-related behaviours in AD mouse models is unknown. The objective of this project was to compare anxiety-related behaviours between the hAPP-J20 (Aβ pathology) and PS19 (Tau pathology) mouse models of AD and determine whether PTP1B is involved in these behaviours. Another major objective of this project was to investigate the role of PTP1B in tau pathology in the PS19 mouse model in anxiety-related brain regions, since this has not been previously examined. Using key anxiety-testing paradigms such as the elevated plus maze (EPM) and the open field test (OF), an age-based dimorphism in the onset of an inappropriately lowered anxiety response in the J20 and PS19 mouse models was identified. Furthermore, it was shown that this abnormal anti-anxiety baseline phenotype could be normalized with selective PTP1B inhibition by the drug trodusquemine and by genetic neuronal ablation. Finally, in PS19 mice at 8 months of age, it was shown that PTP1B blockade has the therapeutic effect of relieving neurotoxic phospho-tau burden and neuroinflammation. Together, these findings suggest that unleashed PTP1B may serve as a potential therapeutic target, with a possible role in AD-associated anxiety-related behaviours and AD pathology.

Although considered as a poison for long time, the importance of selenium as an essential trace element is now well recognized. In proteins, the redox active selenium moiety is incorportated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID) and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The most widely studied selenoenzyme GPx protects various organisms from oxidative stresses by catalyzing the reduction of hydroperoxides by using glutathione (GSH) as cofactor. The chemical aspects of the reduction of hydroperoxide by GPx have been extensively studied with the help of synthetic selenium and tellurium compounds. For example, 2-phenyl, 1, 2-benzoisoselenazol-3(2H)-one, commonly known as ebselen exhibits significant GPx activity by using GSH as cofactor. The anti-inflammatory, antiatherosclerotic and cytoprotective properties of ebselen have led to the design and synthesis of nex GPx mimics for potential therapeutic applications. In the first chapter, the importance of selenium in biochemistry in general and the function of selenoenzyme GPx and its synthetic mimics in particular are discussed. In the second chapter, the importance of ebselen as a GPx mimic and how thiol exchange reaction in the selenenyl sulfide intermediate deactivates its catalytic cycle and the possible ways to overcome thiol exchange reaction are described. The third chapter deals with the first synthetic chemical model that effectively mimics the unusual cyclization of sulfenic acid to a sulfenyl amide in protein Tyrosien Phosphatase 1B(PTP1B). PTP1B is a cysteine containing enzyme where the sulfenic acid (PTP1B-SOH) intermediate produced in response to its oxidation by H2O2 is rapidly converted into a sulfenyl amide species, in which sulfur atom of the catalytic cysteine is covalently bonded to the main chain nitrogen of an adjacent serine residue. This unusual protein modification in PTP1B has been proposed to protect the sulfur centre from irreversible oxidation to sulfinic acid and and sulfonic acids. In the fourth chapter, it is shown that not only the catalytic efficiency of ebselen but also its phosphatase like behavior is important for its antioxidant activity. Ebselen is regenerated from selenenic acid (R-SeOH) under a verity of conditions, which protects its selenium centre from irreversible oxidation and thus reduces its toxicity. The fifth chapter deals with spirodizaselenurane and Spirodiazatellurane. Although the chemistry of spirodioxyselenuranes and spirodiazasulfuranes has been studied extensively due to their interesting structural and stereochemical properties, there is no example of stable spirodiazaselenurane and its tellurium analogues. In the fifth chapter, the synthesis, structure and GPx-like activity of the spirodizzaselenurane and spirodiazatellurane are discussed. In summary, the synthetic sulfenic acids and seleneric acids undergo cyclization to their corresponding sulfenyl amides and selenenyl amides and thus protect their sulfur and selenium centers from irreversible inactivation. We have also observed that selenoxides and telluroxides with nearby amide moieties undergo cyclization to their corresponding cyclic spiro compounds. This unusual transformation of sulfenic acids has been recently discovered in PTP1B. As the redox regulation cycle of PTP1B and the catalytic cycle of GPx are similar we believe that GPx may involve a selenenyl amide intermediate in its catalytic cycle.