ABCA7 is the closest homologue of ABCA1, which is established to play a key role in reverse cholesterol transport. ABCA1 deficiency causes Tangier disease and several ABCA1 modulations have been recently associated with Alzheimers disease. Prior research on ABCA7 focused on its role in macrophage lipid efflux and phagocytosis, however, tissue expression studies in mice revealed that ABCA7 is highly expressed in the brain. The function of ABCA7 in the brain is unknown and the purpose of this thesis was therefore to investigate the potential function of ABCA7 in the brain and the possible implications for Alzheimers disease. This was achieved by using in vitro models that transiently express ABCA7 and in vivo models including ABCA7 knockout (ABCA7 KO) mice and human APP transgenic (APPSwInd Tg) mice. ABCA7 was shown to potently stimulate cholesterol efflux from cells to extracellular apoE acceptors. Additionally, apoE expression was decreased by 20% in the brains of ABCA7 KO mice compared to wild type littermate controls and by 46% in ABCA7-deficient macrophages. In vitro models that stably express human APP protein demonstrated that the transient expression of ABCA7 increased intracellular APP targeting, which led to the inhibition of APP processing and a resultant decrease in the production of Aβ. In addition, ABCA7-deficient macrophages displayed impaired capacity to endocytose and degrade Aβ oligomers. Finally, in aged APPSwInd Tg mice where abundant amyloid plaques were present, ABCA7 expression was significantly decreased by 48%. Since cholesterol homeostasis modulates APP processing, the findings of this thesis suggest that ABCA7 may have a role in maintaining cellular cholesterol homeostasis via cholesterol efflux to apoE acceptors and possibly by regulating intracellular trafficking of specific membrane proteins. In summary, ABCA7 was clearly shown in this thesis to have an effect on Aβ generation, clearance and degradation. Furthermore, ABCA7 expression was also affected by Aβ deposition in the brain. Even though more work is required to further elucidate the exact function of ABCA7, the findings presented in this thesis provide the first clues to the function of ABCA7 in the brain.
| Identifer | oai:union.ndltd.org:ADTP/272546 |
| Date | January 2009 |
| Creators | Chan, Lai Ling Sharon, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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