New Treatment Strategy for Alzheimer’s Disease

摘要 本研究的目标是发现新的、基于机制的药物干预措施。 阿尔茨海默病(AD)，最常见的神经退行性疾病。新出现的数据表明， 表观遗传机制是基因表达模式改变和随后的突触的中心 阿尔茨海默病的功能障碍和行为症状。我们的初步研究显示，血液中的 阿尔茨海默病患者前额叶皮质组蛋白修饰标记H3K4me3及其催化酶Kmt3e 死后组织和Tau转基因AD小鼠模型。我们建议调查以下假设： Kmt3e抑制剂能够通过使基因表达正常化来改善与AD相关的认知障碍 和突触功能。为了测试这一点，将使用AD小鼠模型和AD患者特定的神经元来 结合生化、分子、电生理和行为来解决两个具体目标 接近了。在目标1中，我们将确定Kmt3e靶向药物在认知和治疗方面的潜力。 阿尔茨海默病小鼠模型的突触缺陷。为了将动物研究的结果转化为AD患者，在目标2中， 我们将产生并比较来自AD患者和年龄匹配的对照组受试者的人类神经元， 并检测Kmt3e抑制剂逆转AD人类神经元突触缺陷的能力。结果来自 该项目可能导致新的有效的药物来治疗认知和突触缺陷。 广告。

Summary The goal of this study is to discover novel, mechanism-based pharmacological intervention for Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. Emerging data suggest that epigenetic mechanisms are central to alterations in gene expression patterns and the ensuing synaptic dysfunctions and behavioral symptoms in AD. Our preliminary studies showed significantly elevated levels of histone modification mark H3K4me3 and its catalyzing enzyme Kmt3e in prefrontal cortex from AD human postmortem tissues and Tau transgenic mouse model of AD. We propose to investigate the hypothesis that Kmt3e inhibitors are able to ameliorate cognitive deficits associated with AD by normalizing gene expression and synaptic functions. To test this, both AD mouse models and AD patient-specific neurons will be used to address two specific aims with combined biochemical, molecular, electrophysiological and behavioral approaches. In Aim 1, we will identify the therapeutic potential of Kmt3e-targeting agents on cognitive and synaptic deficits in AD mouse models. To translate the findings from animal studies to AD patients, in Aim 2, we will generate and compare human neurons derived from AD patients and age-matched control subjects, and examine the capability of Kmt3e inhibitors to reverse synaptic deficits in AD human neurons. Results from this project may lead to new and effective pharmacological agents to treat cognitive and synaptic deficits of AD.