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. ? ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Cronican, Andrea A; Fitz, Nicholas F; Carter, Alexis et al. (2013) Genome-wide alteration of histone H3K9 acetylation pattern in mouse offspring prenatally exposed to arsenic. PLoS One 8:e53478
Fitz, Nicholas F; Cronican, Andrea A; Saleem, Muzamil et al. (2012) Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci 32:13125-36
Koldamova, Radosveta; Fitz, Nicholas F; Lefterov, Iliya (2010) The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim Biophys Acta 1801:824-30
Cronican, Andrea A; Fitz, Nicholas F; Pham, Tam et al. (2010) Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol 79:1310-6
Lefterov, Iliya; Fitz, Nicholas F; Cronican, Andrea A et al. (2010) Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. J Biol Chem 285:36945-57
Fitz, Nicholas F; Cronican, Andrea; Pham, Tam et al. (2010) Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci 30:6862-72
Lefterov, Iliya; Fitz, Nicholas F; Cronican, Andrea et al. (2009) Memory deficits in APP23/Abca1+/- mice correlate with the level of A? oligomers. ASN Neuro 1: