Alzheimer's disease (AD) is the most common form of dementia with more than 5.5 million patients in the USA, a number that will quadruple by 2047. The disease can be characterized as an accelerated loss of cognitive functioning to such an extent that it interferes drastically with a person Aim 1. Using second generation high throughput sequencing to assess changes in chromatin modifications induced by nutritional signals and their role in the development and progression of cognitive performance and AD pathology.
Aim 2. To reveal genome-wide changes in LXR binding caused by HFD and thus to identify LXR targets whose transcriptional up- or down-regulation has a role in the development and progression of AD-like phenotype in model mice.

Public Health Relevance

This study will address questions that are important for continuing research in a field highly relevant to human health - Alzheimer's disease and changes in chromatin modifications induced by nutritional signals and their role in the development and progression of this disease. The result from this study will help us to understand the interplay between important genes and proteins involved in cholesterol transport in brain, and how the knowledge about disturbed function of those proteins can help in developing new therapeutic strategies for slowing AD progression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037919-03
Application #
8721296
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Petanceska, Suzana
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$475,000
Indirect Cost
$133,470
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Other Domestic Higher Education
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nam, Kyong Nyon; Mounier, Anais; Fitz, Nicholas F et al. (2016) RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Aβ oligomers. Sci Rep 6:24048
Mounier, Anais; Georgiev, Danko; Nam, Kyong Nyon et al. (2015) Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci 35:11862-76
Fitz, Nicholas F; Tapias, Victor; Cronican, Andrea A et al. (2015) Opposing effects of Apoe/Apoa1 double deletion on amyloid-β pathology and cognitive performance in APP mice. Brain 138:3699-715
Lefterov, Iliya; Schug, Jonathan; Mounier, Anais et al. (2015) RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol Dis 82:132-40
Koldamova, Radosveta; Fitz, Nicholas F; Lefterov, Iliya (2014) ATP-binding cassette transporter A1: from metabolism to neurodegeneration. Neurobiol Dis 72 Pt A:13-21
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; Castranio, Emilie L; Carter, Alexis Y et al. (2014) Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist. J Alzheimers Dis 41:535-49
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; Lefterov, Iliya et al. (2013) Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science 340:924-c
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