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Intracellular organelle deficits driving Alzheimer's disease

细胞内细胞器缺陷导致阿尔茨海默病

基本信息

批准号：
10058739
负责人：
Israel Sekler
金额：
$ 171.76万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058739
关键词：
Abeta clearance Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-42 Attenuated Automobile Driving Autophagocytosis Autophagosome Biochemical Bioenergetics Buffers Calcium Calcium Signaling Cell model Cells Clinical Trials Confocal Microscopy Coupled Coupling Defect Development Disease Disease Progression Dyes Electrophysiology (science)Elements Endoplasmic Reticulum Excision Feedback Fibroblasts Functional disorder Gene Expression Goals Health Histopathology Homeostasis Human ITPR1 gene Image Immunoassay Impaired cognition Impairment Inositol Lead Link Lysosome Proton Lysosomes Measures Mediating Membrane Potentials Memory impairment Mitochondria Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organelles Outcome Output Oxidative Stress Pathogenesis Pathogenicity Pathology Pathway interactions Periodicity Post-Translational Protein Processing Process Proteins Proteolysis Public Health RNA Splicing Regulation Resolution Resources Rest Role Ryanodine Receptor Calcium Release Channel Signal Transduction Site Source Structure Synapses Synaptic Transmission Testing Therapeutic Transcriptional Activation abeta accumulation alkalinity amyloid peptide amyloid structure cellular pathology cognitive function fluorescence imaging hyperphosphorylated tau misfolded protein mitochondrial dysfunction mitochondrial membrane mouse model mutant neuron loss novel therapeutics operation protein aggregation response restoration tau Proteins tau aggregation therapeutic target transcription factor treatment strategy tripolyphosphate two photon microscopy

项目摘要

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by aggregation of β-amyloid (Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated tau, and a progressive loss of cognitive function. While much is known regarding the biochemical composition and structure of amyloid and tau in AD, relatively less focus has been placed on the intracellular handling of detrimental protein products, and more specifically, how upstream deficits in organelle function can accelerate the disease process and directly contribute to memory impairments. While neurons rely on dedicated organelles to execute specific functions and sustain health, several in particular have been linked to AD pathophysiology, including the ER, which is important for protein assembly and intracellular calcium signaling; lysosomes, which are critical for breaking down and removing the cellular debris and misfolded proteins collected by authophagosomes; and mitochondria, which are responsible for the bioenergetics of the cell (Mustaly et al., 2018). In the global operations of maintaining neuronal viability, the functions of these organelles are highly inter-dependent, and they are often physically coupled to one another. Despite the close coupling, their respective roles in contributing to AD have typically been studied in isolation. For example, there are compelling studies detailing aspects of ER, lysosome, or mitochondrial dysfunction in AD, yet substantially less is understood about how altered interactions among these organelles can lead to pathogenic cascades. This isolationist approach may lead to critical oversights in understanding key processes in AD and missing potential therapeutic opportunities. Thus, the overall goal of this study is to identify mechanisms underlying deficiencies in specific organelle functions and examine how this affects their interactions, characterize how this potentiates AD pathology, and establish the upstream drivers of this cascade for consideration as a therapeutic target. This will be accomplished through the following Aims: Aim I: Determine if the AD-associated disruption in ER function disrupts lysosomal dynamics and clearance of aggregated proteins. Aim II: Determine the mechanism by which excess ER-Ca2+ release disrupts mitochondrial function and degradation. Aim III: Establish upstream drivers of intracellular pathogenic cascades and determine if targeting ER-homeostasis will resolve lysosomal and mitochondrial defects. The proposed study will have a significant impact on the field as it will provide new mechanistic information about how misaggregated proteins accumulate in AD and are associated with altered ER signaling. Moreover, targeting specific intracellular organelles may reveal effective new treatment strategies for AD.

阿尔茨海默病（Alzheimer's disease，AD）是一种以β-淀粉样蛋白聚集为特征的神经退行性疾病（Aβ）肽、由过度磷酸化tau组成的神经原纤维缠结以及认知能力的进行性丧失功能虽然关于AD中淀粉样蛋白和tau蛋白的生化组成和结构已知很多，相对较少关注有害蛋白质产物的细胞内处理，具体来说，细胞器功能的上游缺陷如何加速疾病进程，会导致记忆障碍虽然神经元依赖于专门的细胞器来执行特定的功能，维持健康，特别是一些与AD病理生理学有关，包括ER，这是重要的蛋白质组装和细胞内钙信号;溶酶体，这是关键的分解和去除由自噬体收集的细胞碎片和错误折叠的蛋白质;以及线粒体，其负责细胞的生物能量学（Mustaly等人，2018年）。在全球维持这些细胞器的功能是高度相互依赖的，并且它们通常是物理上相互依赖的。彼此相连。尽管紧密耦合，但它们各自在促成AD方面的作用通常被孤立研究。例如，有令人信服的研究详细说明了ER、溶酶体或 AD中的线粒体功能障碍，但对这些线粒体功能障碍之间如何改变相互作用的了解甚少。细胞器可以导致致病级联。这种孤立主义的做法可能会导致关键的疏忽，了解AD的关键过程并错过潜在的治疗机会。因此，本研究旨在确定特定细胞器功能缺陷的潜在机制，并研究这种缺陷是如何发生的。影响它们的相互作用，表征这如何增强AD病理学，并建立将该级联考虑为治疗靶点。这将通过以下目标来实现： I：确定AD相关的ER功能破坏是否破坏溶酶体动力学和聚集蛋白质目的II：确定过量ER-Ca 2+释放破坏线粒体的机制功能和退化。目的III：建立细胞内致病级联的上游驱动因子并确定如果靶向ER-稳态将解决溶酶体和线粒体缺陷。拟议的研究将有一个对该领域的重大影响，因为它将提供有关错误聚集蛋白质如何在AD中积累并与改变的ER信号传导相关。此外，针对特定的细胞内细胞器可能揭示有效的新的治疗策略AD。