CELL AND MOLECULAR PATHOBIOLGY OF ALZHEIMER'S DISEASE

在过去的PPG期间，我们明确地将导致早发性阿尔茨海默病（AD）的基因直接与溶酶体系统内吞和自噬途径中的功能联系起来，记录了从AD早期开始的这些功能的特异性损伤。我们建议进一步验证我们的新概念框架，将溶酶体系统定位为各种遗传和环境ad风险因素破坏的共同主要目标。初步数据支持这一假说，即对阿尔茨海默病内吞和自噬途径中多个位点的累积“撞击”导致囊泡逆行运输和信号传导的选择性失败，包括AP在内的致病性蛋白的清除受损，神经性营养不良和神经变性。这四个项目采用紧密集成的多学科方法来研究溶酶体途径室之间的高度动态相互作用。单个项目主要关注整个溶酶体系统的不同方面-早期内体信号传导的生物学和遗传调控（分别为项目1,4），晚期内体/外泌体生物学（项目3）和自噬/溶酶体功能（项目2）-从而使我们能够全面定义特定的主要ad危险因素如何破坏溶酶体系统并产生显著的致病后果。从单神经元基因分析到视频显微镜和高压免疫金EM成像的创新技术将应用于患者细胞和我们的新型小鼠模型。除了确定AD关键危险因素（APP、胆固醇、早老素、胱抑素C、神经营养因子剥夺）诱导的病理生物学机制外，我们还将为AD的创新治疗方法提供理论基础和验证，包括内吞作用和脂质介导的AD病理调节剂（项目1）、自噬/溶酶体修复（项目2）、基于外泌体的调节和基于胱抑素C的治疗（项目3）。以及APP/神经营养因子信号通路中促进神经元存活的药物靶点鉴定（项目4）。这些新方法中的一种或多种的验证将对阿尔茨海默病和其他主要与衰老相关的神经退行性疾病的治疗方法的实现产生重大影响。

DESCRIPTION (provided by applicant) In the past PPG term, we have unequivocally linked the genes causing early onset Alzheimer's disease (AD) directly to functions' within endocytic and autophagic pathways of the lysosomal system, documenting specific impairment of these functions beginning at the earliest stages of AD. We propose to validate further our novel conceptual framework that positions the lysosomal system as a common primary target for disruption by diverse genetic and environmental AD-risk factors. Preliminary data support the working hypothesis that cumulative "hits" to multiple sites within the endocytic and autophagy pathways in AD cause selective failures of vesicular retrograde transport and signaling, impaired clearance of pathogenic proteins including AP, neurotic dystrophy, and neurodegeneration. The four Projects apply a tightly integrated multidisciplinary approach to study the highly dynamic interplay among lysosome pathway compartments. Individual Projects focus mainly on distinct facets of the entire lysosomal system - the biological and genetic regulation of early endosome signaling (Projects 1, 4 respectively), late endosome/exosome biology (Project 3), and autophagy/lysosome function (Project 2) - thus enabling us to define comprehensively how specific major AD-risk factors disrupt the lysosomal system with significant pathogenic consequences. Innovative technologies from single-neuron gene profiling to video microscopy and high voltage immunogold EM imaging will be applied to patient cells and our novel mouse models. In addition to defining the mechanisms underlying pathobiology induced by key AD-risk factors (APP, cholesterol, presenilin, cystatin C, neurotrophin deprivation), we will provide the rationale and validation for innovative therapeutic approaches to AD, including modulators of endocytosis and lipid-mediated AD pathologies (Project 1), autophagy/lysosomal remediation (Project 2), exosome-based modulation and cystatin C-based therapies (Project 3), and drug target identification within APP/neurotrophin signaling pathways promoting neuron survival (Project 4). Validation for one or more of these new approaches will have significant impact on realizing therapeutics for AD and other major aging-related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Addressing an urgent need for additional perspectives on effective therapies for Alzheimer's Disease, our Program advances a novel biological framework for understanding how AD develops and that identifies new directions for the therapy of AD and possibly other aging-related diseases. Exploiting this framework, we propose to validate multiple innovative therapeutic approaches for AD. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE CORE; Dr. Ralph A. Nixon, Core Leader (CL) DESCRIPTION (provided by applicant): Core A will facilitate the research aims of all projects and cores by providing all necessary administrative support, by fostering collaborative interactions and cross-fertilization of ideas across projects/cores, by facilitating education/training, and recruitment activities, and by providing for internal and external scientific review of the research. To achieve these objectives, the core will: 1) Monitor fiscal activities of the projects and cores, and centralize the administration of clerical and personnel matters. 2) Facilitate communication among investigators within the Program by holding monthly meetings to discuss progress made in each Program component. Communication and quality control will also be enhanced by a system of internal review of research findings prepared for progress reports and manuscripts. 3) Enhance ongoing scientific education and training of Program investigations through a range of seminar series, each involving a multidisciplinary selection of New York area and national/international speakers from the Alzheimer's disease research fields, the neurosciences, and neuroimaging, respectively. 4) Provide for ongoing scientific review of accomplishments, activities, and future directions of this Program Project by an External Advisory Committee of scientific experts. 5) Provide statistical consultation and develop new statistical methodologies as necessary. 6) Identify, recruit and mentor new investigators and trainees whose research can contribute to the long-range aims of this Program Project. Facilitate the use of resources generated through this Program by other investigators. PUBLIC HEALTH RELEVANCE: This Core supplies essentials support for our Program, which advances a novel biological framework for understanding how Alzheimer's disease develops and which identifies new directions for the therapy of AD and possibly other aging-related diseases.