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Exploring the mechanisms by which the kynurenine pathway metabolite quinolinic acid induces phosphorylation of Tau protein

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thesis
posted on 28.03.2022, 22:07 by Ali Asgher Ali
Quinolinic acid (QUIN) is a well-described neurotoxin produced in excess by chronic induction of the kynurenine pathway of tryptophan metabolism. Indeed, clinical evidence supports a role for QUIN in the progression of Alzheimer's disease (AD). Several studies have also shown that QUIN is associated with Tau phosphorylation. QUIN was found to be co-localised with phosphorylated Tau (pTau) in AD brain clinical samples and treatment of primary neurons with QUIN increased the expression of pTau. However, no studies have yet examined the mechanism by which QUIN causes Tau phosphorylation. The work reported in this thesis aimed to better understand this mechanism. Considering that QUIN has been reported to mediate cellular calcium influx by stimulation of the N-methyl D-aspartate receptor (NMDAR) stimulation and that calcium influx also has been shown to lead to Tau phosphorylation, it was hypothesized that QUIN might mediate Tau phosphorylation by increasing intracellular calcium influx. Using a variety of experimental strategies, we investigated whether this was the case. We further explored this mechanistic link by examining the effects of a calcium chelator, an inhibitor of kynurenine-3-monooxygenase (KMO; the enzyme that leads to QUIN production) and NMDAR blockers on the expression of pTau.

History

Table of Contents

1 Introduction -- 2 Methodology -- 3 Results -- 4 Discussion

Notes

Bibliography: pages 77-97 Theoretical thesis.

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

MRes, Macquarie University, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award

2020

Principal Supervisor

David B. Lovejoy

Rights

Copyright Ali Asgher Ali 2020. Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (xvi, 97 pages) illustrations

Former Identifiers

mq:72362 http://hdl.handle.net/1959.14/1284082