ApoE4 in human cortical interneuron degeneration and network activity

项目摘要/摘要 癫痫经常与阿尔茨海默病(AD)有关，但是否有共同的共同之处 机制在很大程度上是未知的。GABA能功能连接性改变所致的网络多动 中间神经元被认为是许多认知障碍的基础，一种“中间神经元疾病”是主要原因。 癫痫的假说。然而，对中间神经元的病理生理学知之甚少，尤其是在 载脂蛋白4相关的AD和癫痫患者。了解载脂蛋白E4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的中间神经元特性 突变。对患者体细胞进行重新编程使其能够重现正常和病态人类 特定条件下的组织发育特性和一种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。AIM 1将测试 ApoE4将导致3D皮质球体中GABA能神经元退化的假说 通过用Dlx1/2-GFP报告标记球体来监测与AD相关的病理 并将这些细胞变化与阿尔茨海默病相关病理联系起来。目标2将测试 ApoE4依赖性退变将导致3D皮质球体过度兴奋的假说 进行多电极阵列记录以测量基线神经活动和暴露后 不同的抗癫痫药。总而言之，这些研究有望提供更好的理解 载脂蛋白E4如何在人类皮质间神经元发育和网络水平上发挥作用 因此有助于理解AD的病理生理学，有助于发现新的 阿尔茨海默病和癫痫的治疗策略。

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.