Molecular Diversity Among Hippocampal and Entorhinal Cells in Aging and Alzheimer's Disease

ABSTRACT Alzheimer’s disease (AD) is the leading cause of dementia (60-80%), affecting tens of millions of people globally and, due to longer lifespans and aging populations, perhaps hundreds of millions more by 2050. AD pathology is first observed in allocortical and limbic areas within the cerebrum, in particular medial temporal cortical regions critical for learning and memory including the hippocampal formation and entorhinal cortex (HIP-EC). Within these areas, pathology exhibits subregional and cell type specificity, with layer 2 of entorhinal cortex and the hippocampal CA1 field (Sommer’s sector) exhibiting pathological hallmarks before dentate gyrus granule cells and other major hippocampal neuronal subtypes. Understanding the molecular basis of this selective vulnerability (and conversely the resilience of other cell types) will provide new insights into the etiology of AD, but to date only limited efforts have been made to understand the molecular signatures differentiating neuronal and non-neuronal cells in HIP-EC. We therefore propose to conduct single nuclear RNA sequencing (snRNA-seq) and single nuclear Assay for Transposase Accessible Chromatin (snATAC- seq) in 5 regions of HIP-EC of AD brains, young/mid adult and aged neurotypical “control” human brains, and young adult and aged rhesus macaque brains. This will allow us to develop a high resolution cell census of HIP-EC which will in turn allow us to identify enriched genes, gene expression patterns, gene regulatory networks, and biological processes potentially mediating cell type specific differences in the AD and aged HIP-EC.