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

项目概要（快速通道申请） 阿尔茨海默病（AD）是一种神经退行性疾病，在美国影响超过540万人。 只有国家。AD的复杂性和多因素性对开发 有效的治疗。针对特定AD相关通路的努力在动物研究中显示出希望， 在人体试验中失败。因此，迫切需要寻找新的治疗靶点，开发新的药物 候选人AD 载脂蛋白（apo）E4是三种apoE亚型（apoE 2，apoE 3，apoE 4）之一，其携带者与 60-80%的AD病例，使apoE 4成为AD的主要遗传风险因素。该提案基于四个 我们对小鼠模型和人诱导多能干细胞（hiPSC）衍生的 表达不同apoE亚型的神经元。首先，apoE 4在基因敲入（KI）小鼠中的表达导致年龄增加， 海马门区GABA能中间神经元的依赖性和细胞自主性损伤， 与海马网络活动缺陷和学习记忆障碍相关。第二、 光遗传学抑制门部GABA能中间神经元活性损害野生型小鼠的空间学习和记忆 提示门部GABA能中间神经元损伤可直接导致认知功能障碍。第三、 用GABAA受体增强剂戊巴比妥或小鼠抑制性神经元移植治疗 在apoE 4-KI小鼠中，向海马门中注入祖细胞挽救了学习和记忆缺陷。第四、 apoE 4表达导致hiPSC衍生的神经元培养物中GABA能中间神经元死亡， AD患者的海马门。总之，这些发现强烈表明，apoE 4导致GABA能 中间神经元损伤，导致学习和记忆缺陷，并代表了一种新的治疗靶点， AD. 我们最近发现了两类能够保护GABA能神经元免受 apoE 4的有害作用该提案旨在进一步开发，优化和验证靶向化合物 apoE 4诱导的GABA能中间神经元损伤作为AD的一种新治疗方法。这个的目标 建议是：1）对初始化合物进行ADME和理化研究， 通过apoE 4-KI小鼠体内海马电生理记录的药效学（PD）标志物，2） 通过构效关系鉴定和优化先导小分子GABA能中间神经元保护剂 相关性研究以及药代动力学和PD研究，以及3）测试小- apoE 4-KI小鼠和携带apoE 4的hiPSC衍生神经元中的分子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.