Acute inhibition of fast organelle transport by amyloid beta peptides

淀粉样β肽对快速细胞器转运的急性抑制

• 批准号: 7680531
• 负责人: James Q Zheng
• 金额: $ 11.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680531
• 关键词: Acute; Adverse effects; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Axon; Axonal Transport; Bathing; Behavioral; Biochemical; Brain; Cell Death; Cell physiology; Cognitive; Condition; Cytoskeleton; Data; Defect; Dendrites; Development; Disruption; Evaluation; Exhibits; Genetic; Goals; Hippocampus (Brain); Image; Immunofluorescence Immunologic; Impairment; Life; Microtubules; Mitochondria; Molecular; Movement; Nerve Degeneration; Nervous System Physiology; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; One-Step dentin bonding system; Organelles; Pathogenesis; Peptides; Pharmaceutical Preparations; Play; Principal Investigator; Process; Production; Resolution; Role; Senile Plaques; Signal Pathway; Signal Transduction; Staging; Structure; Synapses; Testing; Toxic effect; amyloid precursor protein processing; axonopathy; base; cytotoxic; drug development; experience; extracellular; monomer; programs; synaptic function; synaptic inhibition; tau Proteins; trafficking

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a progressive neurodegenerative disease highlighted by two pathological hallmarks: extracellular senile plaques containing amyloid ¿ aggregates and intracellular neurofilbrillar tangles consisting of hyperphosphorylated microtubule-associated tau proteins. Aggregated A¿ fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities of AD brains. Recent studies, however, indicate that A¿ molecules exert adverse effects on neuronal functions independent of cell death. Specifically, soluble A¿ oligomers were found to exhibit severe inhibition of synaptic functions and plasticity, indicating that these intermediate A¿ aggregates, not the fibrils, may be responsible for synaptic deficits in AD brains. At this moment, how A¿ molecules impair synaptic functions remain unknown. It is also not clear whether A¿ molecules exert any adverse effects on other cellular functions independent of cell death. We find that soluble A¿ molecules acutely impair fast transport of mitochondria through a specific signaling pathway involving GSK3¿. Our findings are distinct from the long-term toxic effects of A¿ on neurons and do not involve cell death. Given that mitochondrial trafficking and localization are essential for many cellular functions including synaptic activities, their inhibition by A¿ could play an important role in AD-related dysfunctions of neuronal connectivity. This R21 application is based on these exciting findings and aims to further investigate acute effects of A¿ on neuronal trafficking of mitochondria and other cellular organelles. The central hypothesis is that A¿ molecules exhibit acute inhibition on neuronal trafficking, which may constitute one of the early A¿ adverse effects leading to the disruption of normal neuronal functions and development of AD-related neuronal dysfunctions. The proposed study will specifically take advantage of our high-resolution imaging expertise, the manipulability of cultured hippocampal neurons, and our experience in neuronal signal transduction to investigate the following two aims: (1) To characterize and investigate the acute inhibitory effects of A¿ molecules on trafficking of mitochondria and other organelles; (2) To study the cellular mechanisms underlying A¿ acute impairment of mitochondrial transport involving the GSK3¿ signaling pathway. The goal of this study is to identify the significant adverse effects of A¿ molecules on important neuronal functions that may contribute to AD pathological conditions. Results from this study will not only advance our understanding of AD cellular mechanisms but also provide the signaling mechanisms that can be targeted for drug development for AD prevention and treatment.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种程序性神经培养性疾病，由两个病态RKS突出显示：细胞外的老年斑块conta conta conta conta conta conta conta in ta聚集体和由高磷酸化微管相关的tau蛋白组成的细胞内神经膜缠结。 Fibrils征服了神经退行性的Corprit和随后的认知异常，而近期研究表明a。分子对与细胞死亡无关的神经元功能产生不利影响。发现低聚物表现出严重抑制突触功能和可塑性，表明中间A a。骨料而不是原纤维可能导致AD大脑中的突触缺陷。分子损害突触功能仍然未知。分子对与细胞死亡无关的其他细胞功能发挥任何不利影响。分子通过涉及GSK3的特定信号通路损害线粒体快速运输我们的发现不同于A检测的长期毒性作用关于神经元，不细胞死亡。她可以在神经元连接的广告相关功能中发挥重要作用。关于线粒体和其他细胞细胞器的神经元运输。分子表现出对神经元贩运的急性抑制作用，这可能会征集早期a。对神经元功能的破坏和与AD相关的神经元功能障碍的不利影响。 A关于线粒体和其他细胞器的分子；涉及GSK3的线粒体运输的急性损害信号通路。进口分子可能有助于AD地窖机制的G，但也是信号传导机制，用于预防AD的药物开发。