The underlying quantitative variation in susceptibility to develop Alzheimer's disease (AD) is controlled by multiple genes, environmental factors, and metabolic signals. Importantly, some metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, follow certain dietary patterns and lifestyle, and are associated with increased risk of dementia and AD at advanced age. The detrimental effects of high fat diet (HFD) on cognitive performance and exacerbation of cerebral amyloidosis and amyloid angiopathy has been recently demonstrated in an animal model of AD. Equally important, exposure to some toxic environmental factors, such as drinking water arsenic (As), induces changes that are indistinguishable from, or coincide with pathological and clinical features of AD including: induced tau hyperphosphorylation, upregulation of amyloid precursor protein (APP);increased cardiovascular disease;enhanced brain inflammatory reactions, hyperinsulinemia in mice, and cognitive and memory deficits. It is completely unknown, however, whether HFD and environmental exposures combine to increase AD risk and disease progression. Emerging research and novel findings of epigenetic reprogramming inflicted by dietary agents or As exposure strongly suggest that induced changes in histone marks are retained throughout the life and accumulate to promote AD pathogenesis. Thus age dependent gene-environment interactions are critical for the development and progression of late onset AD (LOAD). It is therefore hypothesized that the combined impact of HFD and As on epigenetic chromatin modifications results in pathogenic tissue and organ-selective transcriptional activity that translates into increased risk of developing, accelerating or aggravating AD phenotypes. The objectives of the proposed research are: 1) In a well-established animal model for AD, to reveal organ specific changes in chromatin modifications in brain and liver, instigated by the collective effect of HFD and As exposure that produce genome wide pathogenic transcriptional activity, and 2) To reveal changes specific for AD phenotype (cognitive performance, amyloid deposition in brain parenchyma, metabolic abnormality and blood vessel wall remodeling) caused by combined exposures that result from identified changes in histone modifications. This goal will be achieved by accomplishing the following Specific Aims:
Aim 1 : To reveal the consequences of collective exposure to HFD and As on AD phenotype and lipid and glucose metabolism;
and Aim 2 : To assess changes in chromatin modifications in brain and liver induced by HFD and As in AD mice and to correlate specific changes in the epigenome to behavioral deficits and brain amyloidosis.

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 and environmental signals specifically after arsenic exposure, 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 of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES021243-02
Application #
8538388
Study Section
Special Emphasis Panel (ZES1-LWJ-J (DI))
Program Officer
Kirshner, Annette G
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$233,378
Indirect Cost
$79,102
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
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
Fitz, Nicholas F; Castranio, Emilie L; Carter, Alexis Y et al. (2014) Improvement of memory deficits and amyloid-? clearance in aged APP23 mice treated with a combination of anti-amyloid-? antibody and LXR agonist. J Alzheimers Dis 41:535-49
Lefterov, Iliya; Koldamova, Radosveta (2014) Metabolic Disorders and Neurodegeneration, introduction to the special issue. Neurobiol Dis 72 Pt A:1-2
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; 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