Date of Award

2012

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical Sciences

Faculty

Computing, Health and Science

First Advisor

Professor Ralph Martins

Second Advisor

Dr. Giuseppe Verdile

Third Advisor

Dr. Sherif Boulou

Abstract

CD147, also known as basigin, extracellular matrix metalloproteinase inducer, neurothelin, tumour cell-derived collagenase stimulatory factor, M6, HT7, OX47 or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues with high expression in the hippocampus, pre-frontal cortex, thyroid, heart, early erythroid, amygdala and placenta. This protein is involved in various cellular and biological functions such as lymphocyte migration and maturation, tissue repair, cancer progression, T and B lymphocyte activation and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with with cyclophilin A, cyclophilin B, sterol carrier protein, caveolin-1 and integrins, and can influence beta amyloid peptide levels, a protein that is central to Alzheimer’s disease pathology.

Mechanisms through which CD147 regulates bata amyloid levels still remain unclear, thus the current study investigated the impact of high cholesterol and beta amyloid 42 loading on CD147 expression in rat primary cortical neuronal cultures. Its expression in human brain tissue from Alzheimer’s disease and non-Alzheimer’s disease dementias and APPswe transgenic mice fed on a high fat/high cholesterol diet were also determined. CD147 over expression experiments in rat primary cortical neuronal and SH-SY5Y cultures using recombinant adenoviruses (AdRSV-CD147 and AdRSV-Empty) in the presence and/or absence of cyclophilin A were employed to determine level of proection against oxidative stress and toxicity. Finally sequencing of the CD147 promoter region (-392 to -242 nucleotides) was perfomed to identify possible single neucrotide polymorphysims that may be linked to Alzheimer’s disease pathology.

The in vitro experiments conducted in this study have shown that cholesterol and beta amyloid loading and oxidative stress result in increased CD147 expression in rat primary cortical neuronal cultures and that CD147 protects neuronal cultures from beta amyloid toxicity only in the presence of cylophilin A. However in vivo experiments in animal model have shown that a high fat/high cholesterol diet does not affect brain CD147 levels as evidenced by unchanged expression levels in APPswe mice.

Human studies have revealed a correlation between CD147 and γ-secretase complex components (nicastrin and presenilin 1) in the hippocampus. However, there is no difference in CD147 protein expression between hippocampus and frontal cortex from Alzheimer’s disease patients. Sequencing of the CD147 promoter region, where sterol carrier protein binds to initiate CD147 transcription, has identified two novel single neucrotide polymorphysims (-61A>G and 37C>G). However, single neucrotide polymorphysims within this region are not associated with Alzheimer’s disease pathology.