The Abca1 and apolipoproteins regulate cholesterol and phospholipids efflux, and HDL formation. Abca1 ko mice exhibit decreased cholesterol efflux and poorly-lipidated ApoA-l and ApoE. Poor lipidation of apolipoproteins result in their increased catabolism. Recently, studies demonstrated that AD transgenic mice with engineered disruption of Abca1 have an increased level of amyloid deposition and cognitive impairments. LXR regulates the expression of Abca1 and ApoE both in humans and rodents. Treatment of AD transgenic mice with LXR ligands increases the expression of Abca1 and apolipoprotein. This could increase the lipidation of ApoE and ApoA-l which would lead to increased binding of A? to lipid-rich apolipoproteins, eventually decreasing its aggregation. Studies have shown diminished levels of insoluble A? and improved memory after short-term LXR ligand treatment of AD transgenic mice. The goals of this proposal are to demonstrate the role of Abca1 in toxicity and pathological aggregation of Ap and to emphasize the importance of Abca1 in the molecular pathogenesis of AD at a relatively early stage of the disease progression. We hypothesize that LXR ligand treatment will increase Abca1-regulated cholesterol efflux and generation of lipid-rich apolipoproteins that are critical mediators of A? pathology. Altogether the data will provide evidence that LXR treatment can slow AD progression and establish long-term LXR treatment effects. To test the hypothesis we will establish how LXR and Abca1 regulated lipidation of ApoE and ApoA-l influences A? aggregation. We will compare cholesterol and phospholipid content of lipid particles secreted in conditioned media of astrocytes derived from Abca1ko and WT mice treated with LXR ligands. Furthermore, we will determine how the lipidation states of ApoE and ApoA-l affect AP aggregation. In vitro studies will compare how LXR ligands affect AD phenotype and prove that this effect is mediated through Abca1. Comparing APP/Abca1wt and APP/Abca1ko mice treated with LXR ligands for 4 months will demonstrate that Abca1 is essential in mediating LXR effects on amyloid pathology and cognition and determine long-term treatment effects. Specifically, following LXR ligand treatment spatial working memory, reference memory, and fear conditioning will be examined. Cognitive decline will be correlated with amyloid pathology in the brain, cholinergic markers, and concentrations of ApoA-l and ApoE. Finally, based on results from gene array assays brain expression profiles in LXR treated mice will be assembled and correlated to the endpoints determined in the previous subaims. Better understanding the role of cholesterol metabolism in AD pathology will help develop new routes of treatment to slow disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AG034031-03
Application #
8197547
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Petanceska, Suzana
Project Start
2009-12-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$53,942
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Koldamova, Radosveta; Schug, Jonathan; Lefterova, Martina et al. (2014) Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration. Neurobiol Dis 63:107-14
Fitz, Nicholas F; Cronican, Andrea A; Lefterov, Iliya et al. (2013) Comment on ""ApoE-directed therapeutics rapidly clear ?-amyloid and reverse deficits in AD mouse models"". Science 340:924-c
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