Improved carnosic acid congener compounds for Alzheimer’s disease

用于阿尔茨海默病的改进的鼠尾草酸同类化合物 摘要 目前有500万美国人遭受阿尔茨海默病（AD）的毁灭性后果， 不幸的是，由于我们的人口老龄化，这一数字正在增加。虽然一些治疗方法可以降低疾病 没有治疗方法，所有患者都不可避免地会死亡。治疗AD的护理费用预计将 如果没有有效的治疗方法或AD的发展轨迹没有改变，突触功能丧失 与AD中的认知下降相关，并且比斑块或缠结更好地预测AD中的认知丧失。 对神经元的损伤至少部分地通过氧化和亚硝化应激的产生而发生，这是由于 由寡聚体淀粉样蛋白β（Aβ）引发的活性氧/氮物质（ROS/RNS）的过度产生 肽和下游tau蛋白（pTau）的过度磷酸化和聚集。鼠尾草酸（CA），a 酚类二萜在草药迷迭香（Rosmarinus officinalis）中特别丰富，保护神经元， 突触免受氧化应激造成的损伤。除了直接的抗氧化活性，CA属于 一类激活Keap 1/Nrf 2通路的“亲电蛋白原”，上调多种 II相抗氧化和抗炎蛋白通过抗氧化反应元件（ARE）。在体外， CA保护神经元免受Aβ毒性。CA治疗改善了各种行为和组织学缺陷， 转基因AD模型小鼠，而没有显示出显着的副作用。在第一阶段，我们将开发 一种新型的、专有的CA衍生治疗药物，具有改善的生物利用度，可达到治疗水平 每日一次给药。然后，我们将评估这种新型化合物作为治疗性小分子， 治疗AD。

Improved carnosic acid congener compounds for Alzheimer’s disease Abstract Five million Americans currently suffer the devastating consequences of Alzheimer’s disease (AD), and unfortunately, the numbers are increasing due to our aging population. While some treatments can lower disease burden, there is no cure and all patients inevitably succumb. Cost of care for treatment of AD is expected to reach $1.1 trillion without an effective treatment or a change in the trajectory of AD. Loss of synaptic function is associated with cognitive decline in AD and is a better predictor of cognitive loss in AD than plaques or tangles. Damage to neurons occurs at least partially through generation of oxidative and nitrosative stress, due to excessive generation of reactive oxygen/nitrogen species (ROS/RNS) triggered by oligomeric amyloid beta (Aβ) peptide and downstream hyperphosphorylation and aggregation of tau protein (pTau). Carnosic acid (CA), a phenolic diterpene particularly abundant in the herb rosemary (Rosmarinus officinalis), protects neurons and synapses from damage caused by oxidative stress. In addition to direct antioxidant activity, CA belongs to a class of “pro-electrophiles” that activate the Keap1/Nrf2 pathway, upregulating transcription of a broad range of phase II antioxidant and anti-inflammatory proteins through the antioxidant responsive element (ARE). In vitro, CA protects neurons from Aβ toxicity. CA treatment ameliorates various behavioral and histological deficits in transgenic AD model mice, while showing no significant side effects. During this Phase 1 project, we will develop a novel, proprietary CA-derived therapeutic with improved bioavailability to achieve therapeutic levels with once daily dosing. We will then evaluate this novel compound as a therapeutic small molecule for the treatment of AD.