Cell and molecular pathobiology of Alzheimer's Disease

描述（由申请人提供）：本PPG阐述了AD中最早已知的病理生物学、其致病意义及其起源。我们发现早期和强大的异常的内吞-自噬-溶酶体系统（EALS），并建立了直接联系，AD相关基因，β-淀粉样蛋白和神经退行性变。使用新的细胞和小鼠模型，重现这种早期病理具有显着的真实性，我们将通过应用从单细胞基因组学到体内MR神经成像的最先进的方法来定义潜在的机制。PPG有两个核心（动物，分析）和四个项目。第一个项目检查异常内体的功能意义，将晚期内体病理学表征为散发性AD，21三体（Ts 21）和PS-FAD中内吞和自噬功能障碍之间可能的统一联系，并研究风险因素（App，ApoE和胆固醇）在驱动这种病理学中的作用。第二个项目研究了AD，Ts 21和PS-FAD中受损的自噬的基础，以及观察到的PS在自噬介导的蛋白质降解中的重要作用。将研究自噬的神经保护作用，细胞对受损细胞器和内含物的周转机制，并测试体内调节自噬的策略。第三个项目研究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，并防止潜在的细胞毒性后果的溶酶体功能障碍和组织蛋白酶失衡的EALS病理发展的重要性。第四个项目研究与EALS功能障碍的发展相关的基因，使用单细胞RNA微阵列分析在AD和Ts 21脑中的神经元中，在它们发展内体病理之前和发展时，以及当这种病理通过Ts 21模型中App拷贝数的单一变化而逆转时。基因沉默将用于鉴定Ts 21中促进内体和其他AD病理学的新基因。这些补充研究将全面定义AD中的EALS病理生物学，并确定早期AD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.