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.
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.
|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|
|Rogers, Joseph; Mastroeni, Diego; Grover, Andrew et al. (2011) The epigenetics of Alzheimer's disease--additional considerations. Neurobiol Aging 32:1196-7|
|Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine et al. (2011) Epigenetic mechanisms in Alzheimer's disease. Neurobiol Aging 32:1161-80|