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's daily life and activities. AD is a complex trait in that underlying quantitative variation in susceptibility is controlled by multiple genes and environmental factors. Importantly, some of these environmental and metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, which follow certain dietary patterns and lifestyle, are associated with increased risk of dementia and AD at advanced age, only if confronted in midlife. In this respect the epigenetic reprogramming by dietary agents, which change histone modifications and are retained throughout the life, should be considered highly relevant to AD pathogenesis, supporting the idea of age dependent gene-environment interactions as critical for the development and progression of late onset AD (LOAD). The metabolic pathways of cholesterol and phospholipid transport in the periphery and CNS, as well as some rate limiting steps of insulin secretion, are controlled by oxysterol-sensing transcription factors nuclear liver X receptors (LXRs) - LXR? and LXR, through the expression level of their responsive genes. We hypothesize that in the context of AD the response to high fat diet (HFD) is mediated by epigenetic chromatin modification and LXR binding to DNA and is ultimately realized by tissue and organ-selective transcriptional activity. The goal of this proposal has two major aspects:
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 #
4R01AG037919-05
Application #
9104072
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Miller, Marilyn
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Graduate Schools
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Nam, Kyong Nyon; Wolfe, Cody M; Fitz, Nicholas F et al. (2018) Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice. Biochim Biophys Acta Mol Basis Dis 1864:152-161
Nam, Kyong Nyon; Mounier, Anais; Wolfe, Cody M et al. (2017) Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice. Sci Rep 7:4307
Castranio, Emilie L; Mounier, Anais; Wolfe, Cody M et al. (2017) Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury. Neurobiol Dis 105:1-14
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Carter, Alexis Y; Letronne, Florent; Fitz, Nicholas F et al. (2017) Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice. PLoS One 12:e0172161
Nam, Kyong Nyon; Mounier, Anais; Fitz, Nicholas F et al. (2016) RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of A? oligomers. Sci Rep 6:24048
Fitz, Nicholas F; Tapias, Victor; Cronican, Andrea A et al. (2015) Opposing effects of Apoe/Apoa1 double deletion on amyloid-? 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 82:132-140
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

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