Arginine metabolism and tauopathies
Vemula, Pranav Kumar
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Vemula, P. K. (2019). Arginine metabolism and tauopathies (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/9637
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http://hdl.handle.net/10523/9637
Abstract:
Tauopathies refers to a group of neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated tau protein. Whereas Alzheimer’s disease (AD) is an example of secondary tauopathy, frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17) and progressive supranuclear palsy (PSP) are the members of the familial (with microtubule-associated protein tau mutations) and sporadic primary tauopathies respectively. In spite of the growing prevalence and cost of care and management, there is currently no cure for tauopathies. Hence a better understanding of the disease pathogenesis and the underlying mechanisms is needed urgently. L-arginine is a semi-essential amino acid that can be metabolised by nitric oxide synthase (NOS), arginase and arginine decarboxylase to produce a number of bioactive metabolites. Recent research has implicated altered arginine metabolism (and its inter-related urea cycle) in the pathogenesis of AD. The present research was designed to further investigate how the brain (and blood) arginine metabolic profiles changed in primary and secondary tauopathies using transgenic mouse models and post-mortem human brain tissue.
Physiological concentrations of polyamines putrescine, spermidine and spermine play a critical role in maintaining normal cellular functions, including microtubule stability and assembly. As acetylation of polyamines regulates their levels, hence influence their functions, Experiment 1, therefore, modified the existing quantification method aiming to determine the brain tissue concentrations of acetylputrescine, acetylspermidine and acetylspermine. Unfortunately, the assay sensitivity was too low for the brain tissue samples.
Experiment 2 aimed to obtain the brain and blood arginine metabolic profiles in 4-, 9- and 17-months old APP/PS1 mice with chronic amyloid deposition in the brain. The brain profiles showed genotype-related changes in glutamine, spermidine and spermine in APP/PS1 mice mainly at 17 months of age when a very high amyloid plaque load was present. Regarding the plasma profile, there were no or mild age- and genotype-related changes in L-arginine and its five downstream amino acid metabolites, with no data on amines due to equipment unavailability. The results demonstrate a likely shift of brain L-arginine metabolism towards the arginase-polyamine pathway at the advance age point perhaps aiming to produce more higher-order polyamines.
Experiment 3 systematically investigated how the brain arginine metabolic profile changed in 4-, 8- and 12-14-months old PS19 mice bearing human tau P301S mutation. PS19 mice displayed early and/or prolonged increases in L-ornithine and altered polyamine levels with age. There were also genotype- and age-related changes in L-arginine, L-citrulline, glutamine, glutamate and gamma-aminobutyric acid in a region- and/or chemical-specific manner. The results demonstrate a shift of brain metabolism to favour the arginase-polyamine pathway in PS19 tau mice.
Experiment 4 was designed to investigate how brain arginine metabolism changes in patients with AD, FTLD and PSP using post-mortem human superior frontal gyrus and medial temporal gyrus tissues. Interestingly, there was a general pattern of reduced total NOS activity and L-ornithine levels, but increased total arginase activity, in all three disease groups, again indicating a shift of L-arginine metabolism towards the arginase pathway.
Taken together, the results from both human tissue work and animal models demonstrate altered brain arginine metabolism in tauopathies, which merits future research to understand the underlying mechanisms and clinical significance with a focus on its inter-related urea cycle. The profile comparison between experiments has made us speculate that tau pathology may be highly responsible for the observed brain arginine metabolic profile changes in tauopathies. Given the role of polyamines in maintaining microtubule stability and assembly, future research is required to fully understand how the polyamine system changes in tauopathies.
Date:
2019
Advisor:
Liu, Ping; Hu, Zhang
Degree Name:
Doctor of Philosophy
Degree Discipline:
Department of Anatomy
Publisher:
University of Otago
Keywords:
Arginine metabolism; Tauopathies; Alzheimer's disease; Fronto Temporal Dementia; Progressive Supranuclear Palsy; Polyamines; L-ornithine; PS19 mice; APP/PS1 mice
Research Type:
Thesis
Languages:
English
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- Anatomy [221]
- Thesis - Doctoral [3042]