| Summary: | The ATP-Binding Cassette transporter A1 (ABCA1) is a ubiquitously expressed protein that
mediates the efflux of cholesterol and phospholipids from the plasma membrane onto lipid poor
apolipoproteins (apos), such as apoA-l and apoE. Outside the central nervous system (CNS),
this process constitutes the rate-limiting step in the generation of high-density lipoproteins
(HDL). Low levels of HDL and cellular lipid accumulation are the hallmarks of Tangier disease,
a genetic disease caused by mutations in the ABCA1 gene. ABCA1 is also expressed in the
brain, the most cholesterol rich organ in the body. However, previous to this thesis, the role of
ABCA1 in brain cholesterol metabolism had been poorly explored. Furthermore, recent data
indicated that disturbances in cholesterol homeostasis in the CNS may play an important
pathogenic role in the development of Alzheimer Disease (AD). This, in turn, suggested that
ABCA1 may also affect the progression of AD. The overall goal of this work is to gain insights
into the role of ABCA1 in the development of AD neuropathology and brain lipoprotein
metabolism.
This thesis presents original data showing that ABCA1 deficiency results in a dramatic
reduction in brain apoE levels. Because apoE has a demonstrated role in amyloid deposition,
we also studied the effects of ABCA1 deficiency on amyloidogenesis in AD transgenic mice.
We found that the absence of ABCA1 results in increased amyloid deposition despite low levels
of apoE. The observation that ABCA1-deficiency is proamyloidogenic raised the question
whether ABCA1 overexpression may reduce amyloid formation. We thus evaluated AD
neuropathology in AD mice crossed to an ABCA1 bacterial artificial chromosome (BAC)
transgenic mouse model. We found that although ABCA1 expression and apoE levels are
elevated in the brains of ABCA1 BAC mice compared to non-transgenic controls, these effects
were abolished in the presence of AD transgenes. This suggests that overexpression ofphysiologically regulated ABCA1 may be altered in brains with amyloid deposits compared to
amyloid-free brains. These studies thus constitute original contributions to our understanding of
the role of ABCA1 in brain lipid metabolism, and highlight the mechanisms by which ABCA1
may impact the development of AD neuropathology in vivo. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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