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

摘要 阿尔茨海默病（AD）是痴呆症（60-80%）的主要原因，影响数千万人 在全球范围内，由于寿命延长和人口老龄化，到2050年可能会增加数亿人。AD 病理学首先在大脑内的异体皮质和边缘区，特别是内侧颞叶中观察到 对学习和记忆至关重要的皮层区域，包括海马结构和内嗅皮层 （HIP-EC）。在这些区域内，病理学表现出次区域和细胞类型特异性，第2层为细胞膜。 内嗅皮层和海马CA 1区（Sommer区）在 齿状回颗粒细胞和其他主要海马神经元亚型。了解分子 这种选择性脆弱性的基础（以及其他细胞类型的弹性）将提供新的见解 AD的病因学，但迄今为止，只有有限的努力已经了解的分子签名 在HIP-EC中区分神经元和非神经元细胞。因此，我们建议进行单一核试验， RNA测序（snRNA-seq）和转座酶可降解染色质的单核测定（snATAC- seq）在AD脑、年轻/中年和老年神经典型“对照”人脑的HIP-EC的5个区域中，和 年轻成年和老年恒河猴的大脑。这将使我们能够开发一个高分辨率的细胞普查， HIP-EC将使我们能够识别富集的基因，基因表达模式，基因调控 网络和生物过程可能介导AD和老年人中细胞类型特异性差异 HIP-EC。

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.