Metal and protein correlation in the brain and eye in Alzheimer's disease

Hosseinpour Mashkani, Seyed Mostafa

Metal and protein correlation in the brain and eye in Alzheimer's disease

Hosseinpour Mashkani, Seyed Mostafa

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Publication Type:: Thesis
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Hosseinpour Mashkani, Seyed Mostafa
dc.date.accessioned	2023-11-28T00:33:31Z
dc.date.available	2023-11-28T00:33:31Z
dc.date.issued	2023
dc.identifier.uri	http://hdl.handle.net/10453/173593
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Alzheimer's disease (AD) is pathologically characterised by neurofibrillary tangles and amyloid-β oligomerisation, which may be instigated by transition metals dyshomeostasis (Zn, Cu, and Fe). AD diagnosis is intricate, with physicians using expensive and invasive methods, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Hence, significant demand exists for new research to discover a non-invasive diagnostic technique for monitoring AD patients at an early stage. There is growing evidence that monitoring changes in the eye may reflect brain alterations in AD, making the eye a strategic roadmap for diagnosing AD early. Hence, this thesis focused on the anatomical distributions and concentrations of transition metals and zinc transporter proteins (ZnT3 and ZIP3) in the brains and eyes of AD and healthy mice and human samples to investigate the correlation between pathological changes in the eye and brain in AD. Inductively coupled plasma-mass spectrometry (ICP-MS) and laser ablation-ICP-MS (LA-ICP-MS) were used to investigate the age-related changes and anatomical distributions and concentrations of metal ions in the brain and eye of WT and APP/PS1 mice models. The abundance and expression of zinc transporters in the eye and brain of the mice models (WT and APP/PS1) were measured using immunofluorescence (IF) and Western blot. Transition metals and zinc transporters results demonstrated that there was a significant difference between the metal concentrations and zinc transporters abundances in the WT and APP/PS1 mice models (higher transition metals and zinc transporters in the WT than APP/PS1). These results were compared to data collected from human samples (brain and eye). While AD human samples possessed higher transition metal concentrations compared with healthy samples, our protein study revealed that the AD patients had lower zinc transporters abundance than healthy samples. Finally, the use of quantum dot-labelled amyloid-beta as a multimodal imaging tag for high-resolution immunofluorescent imaging followed by quantitative LA-ICP-MS imaging of amyloid plaques in AD was determined to be unsuitable. A high Te background was observed in the human samples which prevented the co-localisation of IF images with the quantitative LA-ICP-MS data. This thesis is the first to report on the distribution and concentration of transition metals and zinc transporter proteins in mice and human eye retinas of individuals with AD. These findings provide invaluable insights into a better understanding of AD pathogenesis and introduce transition metals and proteins in the retina as potential biomarkers for early AD diagnosis and disease progression monitoring.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/173593/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2023 Seyed Mostafa Hosseinpour Mashkani
dc.rights	au.edu.uts.lib/cph
dc.title	Metal and protein correlation in the brain and eye in Alzheimer's disease	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Alzheimer's disease (AD) is pathologically characterised by neurofibrillary tangles and amyloid-β oligomerisation, which may be instigated by transition metals dyshomeostasis (Zn, Cu, and Fe). AD diagnosis is intricate, with physicians using expensive and invasive methods, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Hence, significant demand exists for new research to discover a non-invasive diagnostic technique for monitoring AD patients at an early stage. There is growing evidence that monitoring changes in the eye may reflect brain alterations in AD, making the eye a strategic roadmap for diagnosing AD early. Hence, this thesis focused on the anatomical distributions and concentrations of transition metals and zinc transporter proteins (ZnT3 and ZIP3) in the brains and eyes of AD and healthy mice and human samples to investigate the correlation between pathological changes in the eye and brain in AD. Inductively coupled plasma-mass spectrometry (ICP-MS) and laser ablation-ICP-MS (LA-ICP-MS) were used to investigate the age-related changes and anatomical distributions and concentrations of metal ions in the brain and eye of WT and APP/PS1 mice models. The abundance and expression of zinc transporters in the eye and brain of the mice models (WT and APP/PS1) were measured using immunofluorescence (IF) and Western blot. Transition metals and zinc transporters results demonstrated that there was a significant difference between the metal concentrations and zinc transporters abundances in the WT and APP/PS1 mice models (higher transition metals and zinc transporters in the WT than APP/PS1). These results were compared to data collected from human samples (brain and eye). While AD human samples possessed higher transition metal concentrations compared with healthy samples, our protein study revealed that the AD patients had lower zinc transporters abundance than healthy samples. Finally, the use of quantum dot-labelled amyloid-beta as a multimodal imaging tag for high-resolution immunofluorescent imaging followed by quantitative LA-ICP-MS imaging of amyloid plaques in AD was determined to be unsuitable. A high Te background was observed in the human samples which prevented the co-localisation of IF images with the quantitative LA-ICP-MS data. This thesis is the first to report on the distribution and concentration of transition metals and zinc transporter proteins in mice and human eye retinas of individuals with AD. These findings provide invaluable insights into a better understanding of AD pathogenesis and introduce transition metals and proteins in the retina as potential biomarkers for early AD diagnosis and disease progression monitoring.

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