Epigenetic dysregulation of transposable elements in cognitive impairment and Alzheimer's disease.

Abstract

Aging and cognitive impairment increase the risk for Alzheimer's disease (AD), and growing evidence suggests that transposable elements (TEs) in the genome play a role in aging and AD. The mechanisms of TE dysregulation in this context are unclear, but one possibility is that epigenetic changes, including DNA hypomethylation and/or reduced chromatin structure, underlie age- and AD-related TE activity. Therefore, the purpose of the present study was to generate a resource for studying TE epigenetics in aging and AD, and to use it to determine if epigenetically dysregulated TEs are related to age/AD-relevant clinical outcomes. We performed RNA-seq on peripheral blood samples from 45 healthy older adults, mild cognitive impairment (MCI) and AD dementia patients, and we observed a pattern of undulating TE transcript expression with MCI and AD, similar to previous reports. We then used whole-genome bisulfite sequencing (WGBS) and transposase-accessible chromatin sequencing (ATAC-seq) to characterize global DNA methylation and chromatin accessibility in the same subjects. We found that most TEs that were enriched/dysregulated in our RNA-seq data with MCI and AD could be found within hypomethylated and chromatin-accessible regions of the genome. These TEs included several that have been directly linked to inflammation and disease in humans, and they were related to cognitive/functional diagnosis, age, and biomarkers of inflammation and neurodegeneration in the subjects we studied. Collectively, these findings are consistent with the idea that epigenetic alterations may contribute to TE transcript dysregulation that plays an important role in aging, cognitive decline, and AD.