Epidemiological and clinical studies have suggested a link between cholesterol metabolism and Alzheimer's Disease (AD) pathogenesis. Despite therapeutic potential of this link, mechanisms by which cholesterol metabolism influences AD pathogenesis remain uncertain. Moreover, relatively little is known about drugs that ameliorate AD phenotypes by interfering with cholesterol metabolism. We have been investigating the role of ABCA1, an ATP-binding cassette transporter that mediates cholesterol efflux and generation of high density lipoproteins (HDL), in AD pathogenesis. Mutations in the ABCA1 gene cause severe HDL deficiencies characterized by accumulation of cholesterol in cells and prevalent atherosclerosis. Ligands for Nuclear liver X receptors (LXR) increase ABCA1 levels and have been shown to decrease atherosclerotic lesions in vivo. We and others showed that LXR agonists reduced A? secretion in cell lines and primary neurons in vitro. The specific hypothesis behind this proposal is that ABCA1 affects A? deposition and clearance. Therefore, lack of functional ABCA1 will aggravate AD phenotype. In contrast, upregulation of ABCA1 triggered by LXR agonists will reduce plaque formation in the brain. The hypothesis is based on the following observations: 1) Our recent study established that T0901317 (TO), an agonist of nuclear LXR receptors, reduces A? production in vivo; 2) we and others have demonstrated that ABCA1 overexpression decreases A? secretion in vitro; 3) Our most recent studies show that ABCA1 deficiency in APP transgenic mice leads to an increased deposition of A? in the brain. These findings suggest that ABCA1 plays a role in AD pathogenesis. They also suggest that LXR agonists may be used to prevent or treat Alzheimer's disease. Yet, precise mechanisms and consequence of altered ABCA1 expression and LXRs treatment in A? processing and AD pathogenesis remain unclear.
The specific Aims are designed to provide a comprehensive assessment of the role of ABCA1 in Alzheimer's disease:
Aim 1. To determine the effect of ABCA1 on A? production and clearance.
Aim 2. To characterize the role of ABCA1 in brain lipid homeostasis and how this is related to the progression and exacerbation of AD phenotype in APP23/ABCA1""""""""'' mice.
Aim 3. To examine the effect of the LXR ligand TO on AD phenotype in APP23 mice fed normal and high fat diet. ? ? ?
