The proposed research represents the coordination of a number of existing facilities and resources aimed at defining the role(s) of DNA methylation in the molecular pathology of Alzheimer's disease. We will integrate the expertise of the Coleman/Rogers lab in Alzheimer's disease with the expertise of the Laird lab in DNA methylation to identify DNA methylation sites in a genome wide study of an affected (temporal neocortex) and a minimally affected (cerebellum) brain region of Alzheimer's disease (AD) and non demented control cases. The 550 brains to be utilized in this proposed study will come from the comprehensive and outstanding Brain Bank at Sun Health Research Institute. Since promoter DNA methylation only relates to the potential for gene expression, it may not be a very good predictor of gene expression differences. Consequently, we will determine the relationship between specific sites of DNA methylation and altered expression of specific genes in AD by correlating our DNA methylation data with an existing set of Affymetrix data on gene expression in ~100 normal and AD brains. Finally, to specify cell classes affected we will conduct combined immunohistochemistry and in situ htbridization studies to define cell classes affected by specific DNA methylation/expression changes.

Public Health Relevance

A successful attack on Alzheimer's disease requires two components: 1) early diagnosis and 2) effective treatment that will significantly delay or halt disease progression. The genome wide study of DNA methylation in Alzheimer's disease proposed here will elucidate and extend the previously under appreciated role of a general molecular mechanism in the basic biology of AD and will lead to earlier diagnosis and new approaches to treatment of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-M (53))
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Petanceska, Suzana
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Banner Sun Health Research Institute
Sun City
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Liu, Jie; Siegmund, Kimberly D (2016) An evaluation of processing methods for HumanMethylation450 BeadChip data. BMC Genomics 17:469
Delvaux, Elaine; Mastroeni, Diego; Nolz, Jennifer et al. (2016) Novel method to ascertain chromatin accessibility at specific genomic loci from frozen brain homogenates and laser capture microdissected defined cells. Neuroepigenetics 6:1-9
Mastroeni, Diego; Khdour, Omar M; Arce, Pablo M et al. (2015) Novel antioxidants protect mitochondria from the effects of oligomeric amyloid beta and contribute to the maintenance of epigenome function. ACS Chem Neurosci 6:588-98
Mastroeni, Diego; Delvaux, Elaine; Nolz, Jennifer et al. (2015) Aberrant intracellular localization of H3k4me3 demonstrates an early epigenetic phenomenon in Alzheimer's disease. Neurobiol Aging 36:3121-3129
Chouliaras, Leonidas; Mastroeni, Diego; Delvaux, Elaine et al. (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients. Neurobiol Aging 34:2091-9
Berchtold, Nicole C; Coleman, Paul D; Cribbs, David H et al. (2013) Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease. Neurobiol Aging 34:1653-61
Mastroeni, Diego; Chouliaras, Leonidas; Grover, Andrew et al. (2013) Reduced RAN expression and disrupted transport between cytoplasm and nucleus; a key event in Alzheimer's disease pathophysiology. PLoS One 8:e53349
Delvaux, Elaine; Bentley, Karen; Stubbs, Victoria et al. (2013) Differential processing of amyloid precursor protein in brain and in peripheral blood leukocytes. Neurobiol Aging 34:1680-6
Rogers, Joseph; Mastroeni, Diego; Grover, Andrew et al. (2011) The epigenetics of Alzheimer's disease--additional considerations. Neurobiol Aging 32:1196-7
Chapman, Robert M; Mapstone, Mark; McCrary, John W et al. (2011) Predicting conversion from mild cognitive impairment to Alzheimer's disease using neuropsychological tests and multivariate methods. J Clin Exp Neuropsychol 33:187-99

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