ApoE4 in human cortical interneuron degeneration and network activity

ApoE4 在人类皮质中间神经元变性和网络活动中的作用

• 批准号: 9916999
• 负责人: Jenny Hsieh
• 金额: $ 41.21万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916999
• 关键词: 3-Dimensional; Abeta synthesis; Activities of Daily Living; Address; Alzheimer' s Disease; Alzheimer' s disease patient; Apolipoprotein E; Astrocytes; Behavior; Biological Models; Brain; Cell Line; Cell physiology; Cells; Cognition; Cognition Disorders; Complex; Data; Development; Disease; Epilepsy; Exhibits; Functional disorder; Genes; Genetic Polymorphism; Genotype; Glutamates; Goals; Human; Human Genetics; Hyperactive behavior; Impaired cognition; Impairment; Individual; Interneurons; Investigation; Knock-in Mouse; Label; Lead; Link; Measures; Mediating; Modeling; Molecular; Monitor; Mutation; Nerve Degeneration; Nerve Regeneration; Neurons; Organ; Organoids; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Play; Population; Property; Protein Isoforms; Public Health; Reporter; Research; Research Proposals; Role; Seizures; Somatic Cell; Structure; System; Testing; Therapeutic; Time; United States; Ventricular; apolipoprotein E-3; apolipoprotein E-4; base; behavioral impairment; confocal imaging; drug development; drug discovery; excitatory neuron; genetic risk factor; human disease; human model; human tissue; improved; induced pluripotent stem cell; inhibitory neuron; innovation; insight; multi-electrode arrays; nerve stem cell; new therapeutic target; novel; novel therapeutics; programs; relating to nervous system; repaired; risk variant; tau phosphorylation

PROJECT SUMMARY/ABSTRACT Epilepsy is frequently associated with Alzheimer's Disease (AD), but whether there are shared common mechanisms is largely unknown. Network hyperactivity due to altered functional connectivity of GABAergic interneurons is believed to underlie many cognitive disorders and a “disease of interneurons” is the major hypothesis for epilepsy. However, little is known about the pathophysiology of interneurons particularly in patients with Apo4-associated AD and epilepsy. Understanding the role of ApoE4 in interneuron dysfunction requires direct investigation of interneuron properties in human neurons derived from patients with these mutations. Reprogramming patient somatic cells enables recapitulation of normal and pathological human tissue developmental properties in defined conditions and a new way to identify the cellular processes underlying complex human diseases, which can lead to mechanism-based drug discovery. Aim 1 will test the hypothesis that ApoE4 will cause degeneration of GABAergic neurons in 3D cortical spheroids which is associated with AD-related pathology by labeling spheroids with a Dlx1/2-GFP reporter to monitor interneuron behavior and correlating these cellular changes with AD-related pathology. Aim 2 will test the hypothesis that ApoE4-dependent degeneration will lead to hyperexcitability in 3D cortical spheroids by performing multi-electrode array recordings to measure baseline neural activity and after exposure with different anti-seizure drugs. Together, these studies are expected to provide a greater understanding of how ApoE4 functions in human cortical interneuron development and function at the network level, therefore contributing to the understanding of the pathophysiology of AD, which could help uncover new strategies to treat patients with AD and epilepsy.

项目总结/摘要 癫痫常与阿尔茨海默病（AD）有关，但是否有共同的共同点， 机制在很大程度上是未知的。GABA能神经元功能连接改变导致的网络活动过度 interneurons被认为是许多认知障碍的基础，“interneurons疾病”是主要的 癫痫病的病因然而，关于中间神经元的病理生理学知之甚少，特别是在 Apo 4相关AD和癫痫患者。了解ApoE 4在中间神经元功能障碍中的作用 需要直接研究来自这些患者的人类神经元中的中间神经元特性， 突变。重编程患者体细胞能够重演正常和病理人类 在确定的条件下的组织发育特性和识别细胞过程的新方法 潜在的复杂的人类疾病，这可能导致基于机制的药物发现。目标1将测试 ApoE 4将导致3D皮质球状体中GABA能神经元变性的假设， 通过用Dlx 1/2-GFP报告基因标记球状体来监测与AD相关病理学相关的 中间神经元的行为和关联这些细胞的变化与AD相关的病理。目标2将测试 假设ApoE 4依赖性变性将导致3D皮质球状体过度兴奋， 进行多电极阵列记录以测量基线神经活动， 不同的抗癫痫药物总之，这些研究预计将提供更好的理解， ApoE 4如何在人类皮层中间神经元发育中发挥作用以及在网络水平上发挥作用， 因此有助于了解AD的病理生理学，这可能有助于发现新的 治疗AD和癫痫患者的策略。