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

摘要 阿尔茨海默病(AD)是导致痴呆症的主要原因(60%-80%)，影响着数千万人 在全球范围内，由于寿命延长和人口老龄化，到2050年，可能还会增加数亿人。广告 病理首先观察到大脑内的局部皮质和边缘区域，特别是内侧颞叶。 对学习和记忆至关重要的皮质区域，包括海马结构和内嗅皮层 (HIP-EC)。在这些区域内，病理表现出次区域和细胞类型的特异性，第2层为 内嗅皮层和海马CA1区(Sommer‘s区)以前显示出病理特征 齿状回颗粒细胞等主要海马神经元亚型。理解分子 这种选择性漏洞的基础(反之，其他细胞类型的弹性)将提供新的见解 对阿尔茨海默病的病因学进行了深入的研究，但到目前为止，人们对理解分子特征的努力有限 HIP-EC中神经细胞和非神经细胞的分化。因此，我们建议进行单核 转座酶可及染色质的RNA测序(SnRNA-seq)和单核分析 在AD脑、青年/中年成人和老年神经典型对照人脑的HIP-EC的5个区域，以及 青年猕猴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将使我们能够识别丰富的基因、基因表达模式、基因调控 阿尔茨海默病和老年性痴呆细胞类型特异性差异的潜在调节网络和生物学过程 嘻哈-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.