Date of Award

2011

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Exercise, Biomedical and Health Sciences

Faculty

Computing, Health and Science

First Advisor

Professor Ralph Martins

Second Advisor

Dr. Giuseppe Verdile

Third Advisor

Professor Ian Macreadie

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterised by acute memory loss and behavioural symptoms. The AD brain is characterized by the presence of senile amyloid plaques associated with degenerating neurites and inflammatory processes. The major protein component of these amyloid deposits is the amyloid beta (Aβ) protein. The Aβ protein is a 40 or 42 amino acid cleavage product of APP (Amyloid Precursor Protein) which is produced in low levels in the normal ageing brain. Although senile amyloid plaques is the major pathological hallmark of AD brains, accumulating evidence has been presented to show that increased levels of soluble forms of Aβ42 correlate with the clinical manifestations and severity of the disease. Increased accumulation (both intracellular and extracellular) and toxicity of Aβ42 peptide in the brain play pivotal roles in neurodegeneration and loss of memory functions in the AD brain. Therefore reducing the toxicity of Aβ42 and increasing its clearance from the brain has been considered to be main targets for AD therapeutics. The search for a disease modifying therapy for AD has been very difficult with the majority of agents failing in later stages of clinical trials. The incomplete understanding of drug-target mechanisms and the lack of high-throughput screening systems for identifying selective target based drugs have been some of the main issues expressed for the failure of AD drugs. Yeast offer a simple eukaryotic model for studying pathological mechanisms and compared to other models there is availability of various experimental tools applicable for high throughput analysis of protein-protein, gene-gene and gene-protein interactions and associated cellular functions. It can also offer a versatile model for initial screening in drug development for various human diseases, including AD. Yeast models have been utilised for studying AD related proteins including APP and its processing enzymes (secretases) and tau phosphorylation.

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