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

基本信息

批准号：
8443416
负责人：
Huntington Potter
金额：
$ 31.83万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/8443416
关键词：
Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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 Nerve 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 peptide A presenilin receptor research study segregation small molecule synaptic function synaptogenesis tau Proteins therapy development

项目摘要

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：A¿ -引起的病理部分是由A¿引起的抑制特定的 MT 马达，我们建议测试这一假设及其含义。许多神经退行性疾病显示微管运输系统存在缺陷，这突显了其在正常细胞生理学中的重要性。导致家族性 AD 的细胞、突变淀粉样前体蛋白和早老素基因会诱导染色体错误分离和非整倍体，这些过程与微管功能密切相关，其他实验室的证实结果表明，早期 AD 皮层中 30% 的神经元是非整倍体/超二倍体。最近，我们发现添加人体细胞或非洲爪蟾卵提取物后，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驱动蛋白 Eg5、KIF4A 和 MCAK，这三种微管运动驱动蛋白对于有丝分裂纺锤体的正常结构和功能至关重要，并且异常地也存在于神经元中，特别是 Eg5。 APP/PS 转基因小鼠（一种阿尔茨海默氏病模型）的大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，导致有丝分裂缺陷、NMDA 受体远离质膜的错误定位以及 LTP A¿对 LTP 的负面影响，连同我们关于其对微管功能影响的新数据，表明 A¿ AD 中记忆过程的抑制可能部分源自其对特定驱动蛋白的抑制，通过确定将细胞、小鼠脑切片培养物和成年小鼠暴露于 Eg5 和/或 Eg5 化学抑制剂的影响，该驱动蛋白会破坏神经发生和神经可塑性。一个关于 1. 神经毒性，2. 切片培养物中的 LTP，以及 3. 成年小鼠的学习和记忆以及 AD 样神经病理学，拟议的实验将使我们能够得出结论，阿尔茨海默病 A 的能力是否抑制某些微管运动的肽对其对阿尔茨海默病中神经发生和神经元功能的破坏有显着贡献，以及这种运动抑制是否构成 AD 治疗的新靶点。