Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease

项目总结(快速通道应用程序) 阿尔茨海默病(AD)是一种神经退行性疾病，影响着美国540多万人 只有一个州。AD的复杂性和多因素性质为发展提出了独特的挑战 有效的治疗方法。仅在动物研究中，针对特定AD相关通路的努力显示出了希望 在人体试验中失败。迫切需要确定新的治疗靶点和开发新药。 AD的候选人。 载脂蛋白(Apo)E4是载脂蛋白(ApoE)三种亚型(apo2、apoE3、apoE4)之一，其携带者与 60-80%的AD病例，使apoE4成为AD的主要遗传危险因素。这项提议建立在四个基础上 我们对小鼠模型和人类诱导多能干细胞(HiPSC)来源的研究的新发现 表达不同载脂蛋白E亚型的神经元。首先，apoE4在敲入(KI)小鼠中的表达导致年龄- 海马门GABA能中间神经元的依赖性和细胞自主性损伤 与海马网活动缺陷以及学习和记忆障碍相关。第二, 肺门GABA能中间神经元活动的光遗传抑制损害野生型大鼠的空间学习记忆 这表明，肺门GABA能中间神经元损伤可直接导致认知障碍。第三, GABAA受体增强剂戊巴比妥或小鼠抑制性神经元移植治疗 进入海马门的祖细胞可以挽救apoE4-Ki小鼠的学习和记忆缺陷。第四, ApoE4的表达导致HiPSC来源的神经元培养中GABA能中间神经元死亡 阿尔茨海默病患者的海马门。综上所述，这些发现有力地表明，载脂蛋白E4导致GABA能 神经元间损伤，导致学习和记忆障碍，是治疗的新靶点 广告。 我们最近发现了两类能够保护GABA能神经元的小分子 载脂蛋白E4对S的不利影响。该提案旨在进一步开发、优化和验证化合物靶向 载脂蛋白E4诱导GABA能中间神经元损伤作为治疗AD的新途径这样做的目的是 建议1)对初始化合物进行ADME和物理化学研究，并建立 ApoE4-Ki小鼠在体海马电生理记录的药效学(PD)标志物，2) 用构效关系鉴定和优化铅小分子GABA能神经元间保护剂 关系研究以及药代动力学和帕金森病研究，以及3)测试小剂量铅的疗效。 载脂蛋白E4-Ki小鼠及携带载脂蛋白E4的HiPSC来源神经元的GABA能中间神经元保护剂 等位基因。

PROJECT SUMMARY (FAST-TRACK APPLICATION) Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 5.4 million individuals in the United States alone. The complexity and multifactorial nature of AD pose unique challenges for the development of effective therapies. Efforts to target specific AD-related pathways have shown promise in animal studies, only to fail during human trials. There is a pressing need to identify novel therapeutic targets and develop new drug candidates for AD. Carriers of apolipoprotein (apo) E4, one of the three apoE isoforms (apoE2, apoE3, apoE4), are associated with 60–80% of all AD cases, making apoE4 the major genetic risk factor for AD. This proposal builds on four novel findings from our studies of mouse models and human induced pluripotent stem cell (hiPSC)–derived neurons expressing different apoE isoforms. First, expression of apoE4 in knock-in (KI) mice causes age- dependent and cell-autonomous impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with hippocampal network activity deficits and learning and memory impairments. Second, optogenetic inhibition of hilar GABAergic interneuron activity impairs spatial learning and memory in wildtype mice, indicating that hilar GABAergic interneuron impairment can directly cause cognitive deficits. Third, treatment with the GABAA receptor potentiator pentobarbital or transplantation of mouse inhibitory neuron progenitors into the hippocampal hilus rescues the learning and memory deficits in apoE4-KI mice. Fourth, apoE4 expression results in GABAergic interneuron death in hiPSC-derived neuronal cultures and in the hippocampal hilus in AD patients. Together, these findings strongly suggest that apoE4 causes GABAergic interneuron impairment, leading to learning and memory deficits, and represents a novel therapeutic target for AD. We recently identified two classes of small molecules capable of protecting GABAergic neurons from apoE4’s detrimental effects. This proposal aims to further develop, optimize, and validate compounds targeting apoE4-induced GABAergic interneuron impairment as a novel therapeutic approach for AD. The goals of this proposal are 1) to perform ADME and physicochemical studies of the initial compounds and establish a pharmacodynamic (PD) marker by in vivo hippocampal electrophysiological recordings in apoE4-KI mice, 2) to identify and optimize the lead small-molecule GABAergic interneuron protectors through structure-activity relationship studies as well as pharmacokinetic and PD studies, and 3) to test the efficacy of the lead small- molecule GABAergic interneuron protectors in apoE4-KI mice and hiPSC-derived neurons carrying the apoE4 allele.