Regulation of the hippocampal epigenetic DNA methylation clock by choline nutrition in a mouse model of Alzheimer's disease

Boston University Medical Campus, Boston MA

Investigators

Abstract

The high prevalence of age-related dementias including Alzheimer's disease (AD), and the lack of effective therapies, makes the development of preventive measures and treatments for these conditions a high priority for biomedical sciences. We found that an increased supply of the essential nutrient, choline, during early life prevents age-related cognitive decline and ameliorates neuropathologic hallmarks of AD in animal models. Be- cause choline serves as a donor of metabolic methyl groups, we hypothesized that the long-term effects of choline availability during development on adult brain function may be related to altered patterns of DNA meth- ylation (DNAm) ? an epigenetic mechanism for regulation of gene expression. Our data are consistent with this notion. Recent studies provided evidence that methylation of a specific set of DNA CpG sites varies with an in- dividual's age, allowing estimates of aging rates in various tissues, and giving rise to the terms ?DNAm age,? ?DNAm clock? and ?epigenetic clock?. DNAm age may also be altered by disease and environment, including nutrition. The discovery of the DNAm clock as a potential biomarker of aging has provided an intellectual framework for testing of hypotheses that link the epigenome to age-related phenotypes. We propose that the brain epigenetic clock is accelerated by the pathophysiologic mechanisms of AD, and slowed by high choline intake during development. Our aim is to determine the effect of high choline nutrition during development on hippocampal DNAm epigenetic aging in wild type and AD-model (APP.PS1), mice and to correlate these pa- rameters with gene expression patterns, cognitive function, and measures of neuropathology. We will use male and female WT and APP.PS1 mice raised by mothers who consumed diets containing standard or high amounts of choline during gestation and nursing. At 6, 12, and 18 months of age we will assess learning and memory of the mice, and subsequently perform high-resolution DNAm analyses using reduced representation bisulfite sequencing (RRBS) and global gene expression analyses using RNA sequencing (RNA-Seq) in their hippocampi. Using state-of-the-art bioinformatics and statistics tools we will a) Determine DNAm patterns, epi- genetic clock DNAm patterns as well as RNA expression patterns as a function of age, sex, AD-model, and developmental choline intake; b) Correlate differential DNAm patterns within the genomic regions of differen- tially-expressed RNAs in order to identify possible cis-acting regulatory sites; and c) Correlate the DNAm- and the RNA expression changes with cognition and neuropathology. Our comprehensive temporal data sets and analyses will provide novel information on the plasticity of the DNA methylome, including the DNAm clock, in WT and AD-model mice in response to availability of choline in early life, and will characterize the relationships of these epigenomic events to transcriptomic, cognitive, and neuropathological measures. The demonstration that the epigenetic clock predicts the trajectory of cognitive aging, and that timely intervention can alter that tra- jectory, will be invaluable in the design of therapeutic strategies to delay age-associated dementias.