CTS-TEs-ADprogress · Cell type-specific molecular analysis of epigenetic changes and transposable element derepression in Alzheimer's disease progression

Cell type-specific molecular analysis of epigenetic changes and transposable element derepression in Alzheimer's disease progression

Alzheimer’s disease (AD) is a major contributor to disease burden and healthcare costs worldwide. AD is usually diagnosed once symptoms like memory impairment become evident. However, at this point typical AD pathology such as Aβ plaques and cell death is already widespread, suggesting that molecular changes have occurred decades before symptom onset. With an increasingly aging population and no available treatments, it has become imperative to identify the molecular mechanisms underlying onset and progression of AD. Chronic environmental stress and age-associated changes in stress response have been associated as drivers of AD pathology. The epigenome plays a critical role in translating stress signals into a cellular response by influencing gene expression, which can either promote or inhibit cell survival. Several studies have shown that alterations in chromatin structure, including heterochromatin loss, and associated changes in gene expression contribute to neurodegeneration. In addition, neuronal death was also linked to transposable element (TE) dysregulation due to epigenetic changes, which can lead to changes in gene expression and insertional mutations due to transposition. However, our understanding of epigenetic changes at onset and during progression of AD pathology is very limited, as current studies have two major limitations: 1) lack of cell type resolution due to use of bulk tissue samples and 2) coverage of only few or only one disease stage. Here, single-cell RNA-seq and ATAC-seq as well as CUT&RUN will be implemented to identify cell type-specific alterations of gene expression and gene regulatory mechanisms during onset and progression of AD pathology in the APPPS1 mouse model. APPPS1 mice are a well-established AD model, which recapitulates many characteristics of preclinical AD in human patients and thereby allows correlating the identified changes with the development of specific pathological hallmarks. Focus of the analysis will be the hippocampus, which is essential for learning and memory and degenerates in AD. Samples will be collected from APPPS1 and wildtype control mice at 6 weeks, 3 months, 9 months and 18 months of age to identify changes across the lifetime of the mice. In addition, the resulting mouse data will be integrated with biomarker and genome-wide association study data from AD patients to identify clinically relevant alterations.

Data: CORDIS, © European Union