Neuronal dysfunction caused by Abeta inhibition of MT motors

Abeta 抑制 MT 马达引起的神经元功能障碍

• 批准号: 8626688
• 负责人: Huntington Potter
• 金额: $ 31.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626688
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Aneuploidy; Brain; Cell division; Cell membrane; Cell physiology; Cell surface; Cells; Chemicals; Chromosome Segregation; Chromosomes; Cognition; Cognitive deficits; Cultured Cells; Data; Defect; Development; Functional disorder; Genes; Genetic Polymorphism; Hour; Human; Kinesin; Lead; Learning; Mammalian Cell; Memory; Microtubules; Mitosis; Mitotic; Mitotic spindle; Motor; Mus; N-Methyl-D-Aspartate Receptors; Natural regeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Neurotransmitters; Pathogenesis; Pathology; Patients; Peptides; Process; Proteins; Recombinants; Signaling Molecule; Slice; Structure; Synapses; System; Testing; Time; Transgenic Mice; Vesicle; Xenopus; egg; familial Alzheimer disease; inhibitor/antagonist; insight; interest; macromolecule; memory process; monastrol; mouse model; mutant; neurogenesis; neuronal cell body; neuropathology; neurotoxic; neurotoxicity; novel; presenilin; receptor; research study; segregation; small molecule; synaptic function; synaptogenesis; tau Proteins; therapy development

DESCRIPTION (provided by applicant): Microtubule (MT) dysfunction, neurotoxicity, chromosome mis-segregation, and defective neuronal plasticity are all induced by A¿ peptide and implicated in Alzheimer's disease (AD) pathogenesis. Our recent data support the unifying hypothesis that A¿-induced pathologies are caused in part by A¿ inhibiting specific MT motors, and we propose to test this hypothesis and its implications. Microtubules serve as the highways upon which ATP driven motor proteins move key cellular components such as proteins, vesicles, chromosomes and large macromolecules, including microtubules themselves, from one part of the cell to another. Many neurodegenerative diseases show defects in the microtubule transport system, underlining its importance in normal cellular physiology. Previously, we found that in AD patients, tg mice, and cultured cells, mutant amyloid precursor protein and presenilin genes that cause familial AD induce chromosome mis-segregation and aneuploidy, processes that are intimately involved with microtubule function. Confirmatory results from other labs showed that 30% of neurons in early AD cortex are aneuploid/ hyperdiploid. Recently, we found that after addition to human cells or Xenopus egg extracts, A¿ impairs the formation and stability of mitotic spindles and directly inhibits three microtubule motor kinesins, Eg5, KIF4A and MCAK, which are essential for the normal structure and function of the mitotic spindle, and, remarkably, are also present in neurons. In particular, Eg5 has severely reduced activity in extracts from brains of the APP/PS transgenic mice, a model of Alzheimer's disease, is inhibited in neurons treated with A¿, and harbors polymorphisms that increase AD risk. Chemical inhibition of Eg5 results in mitotic defects, mis-localization of the NMDA receptor away from the plasma membrane, and inhibition of LTP. A¿snegative impacton LTP, together with our new data regarding its influence on microtubule function, suggests that A¿ inhibition of memory processes in AD may derive in part from its inhibition of specific kinesins, which can disrupt both neurogenesis and neuroplasticity. By determining the effects of exposing cells, mouse brain slice cultures, and adult mice to chemical inhibitors of Eg5 and/or to A¿ on 1. Neurotoxicity, 2. LTP in slice cultures, and 3. learning and memory and AD-like neuropathology in adult mice, the proposed experiments will allow us to conclude whether or not the ability of the Alzheimer A¿ peptide to inhibit certain microtubule motors contributes importantly to its disruption of neurogenesis and neuronal function in Alzheimer's disease and whether such motor inhibition constitutes a novel target for AD therapy.

描述（由应用提供）：微管（MT）功能障碍，神经毒性，染色体错误脱位和缺陷的神经元可塑性均由A肽诱导并在阿尔茨海默氏病（AD）的发病机理中暗示。我们最近的数据支持以下统一的假设：A诱导的病理部分是由于A抑制特定的MT电机而引起的，我们建议检验该假设及其含义。微管用作ATP驱动运动蛋白的高速公路，将关键的细胞成分移动，例如蛋白质，蔬菜，染色体和大型大分子，包括微管本身，从细胞的一部分到另一部分。许多神经退行性疾病在微管传输系统中显示出缺陷，强调了其在正常细胞生理中的重要性。以前，我们发现在AD患者，TG小鼠和培养的细胞中，引起农场AD的突变淀粉样蛋白前体蛋白和寄生虫基因诱导染色体脱粒化和非整倍性，这些过程与微管功能密切相关。其他实验室的确认结果表明，早期AD皮层中有30％的神经元是非整倍体/高二倍体。最近，我们发现，除了人类细胞或爪蟾卵提取物之后，A损害有丝分裂纺锤体的形成和稳定性，并直接抑制三种微管运动动力蛋白EG5，KIF4A和MCAK，这对于有丝分裂脊柱的正常结构和功能至关重要，并且在神经元中也存在于神经元中。特别是，EG5在App/PS转基因小鼠的大脑中的提取物（一种阿尔茨海默氏病模型）的活性严重降低，在接受A研究治疗的神经元中被抑制，并具有增加AD风险的多态性。 EG5的化学抑制会导致有丝分裂缺陷，NMDA受体脱离质膜的错误定位以及LTP的抑制作用。 Snegative Impacton LTP以及我们有关其对微管功能的影响的新数据表明，a对AD中的记忆过程的抑制可能部分来自其对特定驱动蛋白的抑制，这可能会破坏神经发生和神经塑性。通过确定曝光细胞，小鼠脑切片培养物和成年小鼠对EG5和/或A的化学抑制剂的影响1。1。神经毒性，2。LTP在切片培养物中，以及3。学习，记忆和记忆以及成人小鼠中的学习和AD样神经病理学，提议的实验将允许某些显微镜在某些能力中，是否包括Alzheimimub of Alzheimer At apept of Alzheimer Athe a的动态。重要的是，其在阿尔茨海默氏病中的神经发生和神经元功能的破坏以及这种运动抑制是否构成AD治疗的新靶标。