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（由申请人提供）：微管（MT）功能障碍、神经毒性、染色体错误分离和神经元可塑性缺陷均由A肽诱导，并与阿尔茨海默病（AD）发病机制有关。我们最近的数据支持统一的假设，即A？诱导的病理部分是由A？抑制特定的MT电机引起的，我们建议测试这一假设及其影响。 微管充当ATP驱动的马达蛋白将关键细胞组分如蛋白质、囊泡、染色体和大分子（包括微管本身）从细胞的一个部分移动到另一个部分的高速公路。许多神经退行性疾病显示微管转运系统的缺陷，强调了其在正常细胞生理学中的重要性。以前，我们发现，在AD患者，tg小鼠，培养细胞，突变淀粉样前体蛋白和早老素基因，导致家族性AD诱导染色体错误分离和非整倍体，与微管功能密切相关的过程。其他实验室的鉴定结果表明，AD早期皮质中30%的神经元为非整倍体/超二倍体。最近，我们发现，在加入人类细胞或非洲爪蟾卵提取物后，A？会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驱动蛋白Eg 5、KIF 4A和MCAK，这三种蛋白对有丝分裂纺锤体的正常结构和功能至关重要，值得注意的是，它们也存在于神经元中。特别是，Eg 5在APP/PS转基因小鼠（阿尔茨海默病模型）的脑提取物中的活性严重降低，在用A？处理的神经元中受到抑制，并且具有增加AD风险的多态性。Eg 5的化学抑制导致有丝分裂缺陷、NMDA受体远离质膜的错误定位和LTP的抑制。A？Snegative impacton LTP，以及我们关于其对微管功能影响的新数据表明，AD中记忆过程的抑制可能部分来自其对特定驱动蛋白的抑制，这可以破坏神经发生和神经可塑性。 通过确定暴露细胞，小鼠脑切片培养物和成年小鼠Eg 5和/或A？的化学抑制剂对1.神经毒性，2.切片培养中的LTP，以及3.在成年小鼠的学习和记忆以及AD样神经病理学中，所提出的实验将使我们能够得出结论，阿尔茨海默A肽抑制某些微管马达的能力是否对阿尔茨海默病中神经发生和神经元功能的破坏有重要贡献，以及这种马达抑制是否构成AD治疗的新靶点。