Acute inhibition of fast organelle transport by amyloid beta peptides

描述(申请人提供)：阿尔茨海默病(AD)是一种进行性神经退行性疾病，具有两个病理特征：细胞外含有淀粉样聚集体的老年斑和细胞内由过度磷酸化的微管相关tau蛋白组成的神经丝缠结。聚集的A？纤维构成神经性斑块的核心，被认为是AD大脑神经退行性变和随后的认知异常的主要罪魁祸首。然而，最近的研究表明，A分子对神经元功能的不利影响不依赖于细胞死亡。具体地说，发现可溶性A？寡聚体严重抑制了突触功能和可塑性，表明这些中间A？聚集体，而不是纤维，可能是导致AD脑内突触缺陷的原因。目前，A分子是如何损害突触功能的尚不清楚。目前也不清楚A分子是否对细胞死亡以外的其他细胞功能产生任何不利影响。我们发现，可溶性A‘分子通过涉及GSK3’的特定信号通路严重损害线粒体的快速运输。我们的发现与A？对神经元的长期毒性效应不同，也不涉及细胞死亡。鉴于线粒体的运输和定位对包括突触活动在内的许多细胞功能都是必不可少的，A？对线粒体的抑制可能在AD相关的神经元连接功能障碍中发挥重要作用。这项R21的应用基于这些令人兴奋的发现，旨在进一步研究A？对线粒体和其他细胞细胞器的神经元运输的急性影响。中心假设是A分子表现出对神经元运输的急性抑制，这可能是A分子早期不良反应之一，导致正常神经元功能中断和AD相关神经元功能障碍的发展。这项拟议的研究将特别利用我们的高分辨率成像专业知识、培养的海马神经元的可操作性和我们在神经元信号转导方面的经验来研究以下两个目标：(1)表征和研究A？分子对线粒体和其他细胞器运输的急性抑制作用；(2)研究A？急性线粒体运输障碍的细胞机制，涉及GSK3信号通路。这项研究的目的是确定A分子对重要神经功能的显著不利影响，这些影响可能与AD的病理状况有关。这一研究结果不仅有助于我们对AD细胞机制的理解，还将为AD防治药物的开发提供靶向的信号机制。

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.