Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis

项目总结项目1 这项提案的首要目标是确定推动启动和 阿尔茨海默病(AD)的进展。目前迫切需要预防和治疗阿尔茨海默病。我们假设 阿尔茨海默病的遗传风险赋予了生命早期的疾病发病机制，这将通过研究分子和 青春期之前的细胞事件将为预防提供信息。通过采用一种模型系统 更真实地概括了遗传、分子、细胞、生理、解剖和结构组织 对于灵长类动物的大脑，我们将能够识别AD的潜在驱动因素，并更好地模拟疾病发病机制 和进展，以预防疾病。为支持这些目标，本项目(项目1)旨在确定 阿尔茨海默病发生和发展的早期灵长类特异性分子决定因素 携带早老素1(PSEN1)基因工程的绒猴有风险，这是一种早发性AD突变。这个 PSEN1绒猴模型提供了评估分子、细胞和 从出生到婴儿期、青春期和衰老的系统水平。该项目的具体目标是：1) PSEN1突变绒猴与健康年龄匹配和正常老年人的疾病轨迹比较 使用已建立的和正在出现的AD生物标志物进行对照；2)进行全面的行为 通过纵向多模式研究PSEN1绒猴模型与健康对照的关系 从神经发育到寿命的表型特征；以及3)研究分子 来自成纤维细胞的神经细胞作为脑的替代物的特征。通过这些具体目标，我们 预计已经全面表征了第一个阿尔茨海默病基因工程绒猴模型 概述了在AD患者中观察到的与AD相关的表型的频谱，包括行为、认知、 使用翻译方法的生物标记物和神经病理特征；识别早期分子变化 在细胞水平上使用多种组学方法，在坦率的AD神经病理和 认知衰退；并为利用基因工程绒猴创造了知识基础 将AD风险变量作为经过验证的模型。

PROJECT SUMMARY PROJECT 1 The overarching aims of this proposal are to identify the initial cascade of events that drive the inception and progression of Alzheimer’s Disease (AD). There is an urgent need to prevent, and treat AD. We hypothesize that genetic risk for AD confers disease pathogenesis in early life that will be detected by studying molecular and cellular events before the age of adolescence which will inform prevention. By employing a model system that more faithfully recapitulates the genetic, molecular, cellular, physiological, anatomical and structural organization of the primate brain, we will be able to identify underlying drivers of AD and better model disease pathogenesis and progression in order to prevent disease. In support of these goals, this project (Project 1) aims to identify the early life primate-specific molecular determinants of Alzheimer’s disease emergence and progression using marmosets genetically engineered with the presenilin 1 (PSEN1) risk variant, an early onset AD mutation. The PSEN1 marmoset models provide the ability to evaluate divergent changes at the molecular, cellular, and systems level from birth through infancy, adolescence, and aging. The Specific Aims of this project are: 1) to evaluate the disease trajectory of PSEN1 mutant marmosets relative to healthy age-matched and normal aged controls using established and emerging AD biomarkers; 2) to conduct comprehensive behavioral characterization of the PSEN1 marmoset models relative to healthy controls via longitudinal multimodal phenotypic characterization from neurodevelopment through lifespan; and 3) investigate the molecular signatures of neuronal cells derived from fibroblasts as a surrogate to brain. Through these specific aims, we expect to have comprehensively characterized the first genetically engineered marmoset models of AD that recapitulates the spectrum of AD-related phenotypes observed in AD patients for behavioral, cognitive, biomarker, and neuropathological hallmarks using translational approaches; identified early molecular changes at the cellular level using multi-omics approaches prior to the emergence of frank AD neuropathology and cognitive decline; and created the foundation of knowledge for the utility of genetically engineered marmosets with AD risk variants as validated models.