Cell and molecular pathobiology of Alzheimer's Disease

描述（由申请人提供）：本PPG涉及AD最早已知的病理生物学，其致病意义及其起源。我们发现了早期和强烈的内吞-自噬-溶酶体系统（EALS）异常，并建立了与ad相关基因、β -淀粉样蛋白形成和神经变性的直接联系。利用新颖的细胞和小鼠模型，再现这种早期病理，具有显著的真实性，我们将通过应用最先进的方法，从单细胞基因组学到体内MR神经成像，来定义潜在的机制。PPG有两个核心（动物，分析）和四个项目。第一个项目研究了异常内体的功能意义，将晚期内体病理描述为散发性AD、21三体（Ts21）和PS-FAD中内吞和自噬功能障碍之间可能的统一联系，并研究了危险因素（App、ApoE和胆固醇）在驱动这种病理中的作用。第二个项目研究AD、Ts21和PS- fad自噬受损的基础，并观察到PS在自噬介导的蛋白质降解中的重要作用。自噬的神经保护作用，受损细胞器和包涵体的细胞更新机制，将被研究和策略调节自噬在体内将被测试。第三个项目研究了内源性半胱氨酸蛋白酶抑制剂胱抑素C在调节内吞和自噬功能以及在EALS病理发展过程中防止溶酶体功能障碍和组织蛋白酶失衡的潜在细胞毒性后果中的重要性。第四个项目使用单细胞RNA微阵列分析AD和Ts21大脑神经元在它们发生内体病理之前和发生时，以及Ts21模型中App拷贝数的单一变化逆转这种病理时，研究与EALS功能障碍发展相关的基因。基因沉默将用于鉴定Ts21中促进内体和其他AD病理的新基因。这些补充研究将全面界定阿尔茨海默病中的EALS病理生物学，并确定早期阿尔茨海默病的新治疗靶点。

DESCRIPTION (provided by applicant): This PPG addresses the earliest-known pathobiology in AD, its pathogenic significance, and its origins. We identified early and robust abnormalities of the endocytic-autophagic-lysosomal system (EALS) and have established direct links to AD-related genes, beta-amyloidogenesis and neurodegeneration. Using novel cell and mouse models that reproduce this early pathology with remarkable authenticity, we will define underlying mechanisms by applying state-of-the-art approaches ranging from single cell genomics to in vivo MR neuroimaging. The PPG has two cores (animal, analytical) and four projects. The first project examines the functional significance of abnormal endosomes, characterizes late endosomal pathology as a possible unifying link between endocytic and autophagic dysfunction in sporadic AD, trisomy 21 (Ts21), and PS-FAD, and studies the role of risk factors (App, ApoE, and cholesterol) in driving this pathology. The second project investigates the basis for impaired autophagy in AD, Ts21 and PS-FAD and an observed essential role of PS in autophagy-mediated protein degradation. The neuroprotective role of autophagy, the cell's mechanism for turnover of damaged organelles and inclusions, will be studied and strategies to modulate autophagy in vivo will be tested. The third project examines the importance of the endogenous cysteine protease inhibitor cystatin C in modulating endocytic and autophagic function and in protecting against the potentially cytotoxic consequences of lysosomal dysfunction and cathepsin imbalance as EALS pathology develops. The fourth project investigates genes associated with development of EALS dysfunction using single cell RNA microarray analysis in neurons in AD and Ts 21 brain before and as they develop endosomal pathology and when this pathology is reversed by a single change in App copy number in Ts21 models. Gene silencing will be used to identify new genes in Ts21 that promote endosomal and other AD pathology. These complementary studies will define comprehensively EALS pathobiology in AD and identify new therapeutic targets for early AD.