Role of transposon dysregulation in Alzheimer and aging brains revealed by single-cell genomic and transcriptomic analysis

Project summary Aging in humans is associated with a host of brain diseases, including tumors, age related neurodegeneration, and Alzheimer’s Disease (AD). In many tissues, the aging process leads to a derepression of transposable elements (TEs) that lead to inflammation and cell senescence. Several recent studies have demonstrated that multiple subfamilies of TEs are expressed at higher levels in postmortem AD brain than healthy controls as a direct result of the accumulation of mis-folded Tau proteins characteristic of AD pathology. Many of the hallmarks of AD, including neuroinflammation, heterochromatin remodeling, genomic instability, and the recently implicated T-cell infiltration, can be triggered by the activation of TEs. However, because of the unique epigenomic landscape of different cell types in the brain combined with the dependence of TE mobilization on cell division and other factors, the dynamics and consequences of TE activation are likely cell-type-specific. This study aims to characterize the activation of TEs in the brain during aging and AD and identify the functional consequences of activated TEs at the level of individual cells across multiple cell types and to develop the novel computational tools necessary to answer these questions. The first aim will establish the genomic and epigenomic changes related to TEs during normal aging. This analysis will help both to determine whether TEs are involved in the normal brain aging process and age-related neuronal decline, and to establish the healthy controls for comparison with AD. The second aim will perform similar analysis, this time focusing on AD and including the separation of neurons with and without accumulation of pathogenic Tau. The final aim will measure the transcriptome at the single-cell level for all the samples profiled in the first two aims. This sequencing will allow both the measuring gene expression related to innate and adaptive immune responses and the identification of TE derived sequences capable of triggering those responses. The experimental tools and sequencing technologies now exist to examine these questions, and this study is designed to determine how TE activation impacts normal brain aging and AD. Understanding the relationship between TEs, neuroinflammation, and AD pathology may open the door for new treatments and cures.