2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans

大约520万美国人受阿尔茨海默病（AD）影响， 到2050年，将有100万人受到影响。目前，还没有预防或治疗AD的方法， 在与年龄相关的认知能力下降和认知改善化合物的临床试验中， 成功地找到了有效的治疗方法。尽管做了很多努力，但没有候选人 可以减缓甚至治愈这种毁灭性疾病的发展。虽然大部分 这些努力集中在淀粉样蛋白和tau通路上，我们采取了不同的方法， 方法和有针对性的氧化应激。 氧化应激是一种主要的致病机制，其是临床前 AD的发展和随后的进展，以及一个可能被靶向的 预防性和治疗性。活性氧（ROS）的水平增加， 炎症、线粒体功能障碍和由A β催化的金属氧化还原循环，所有过程 与AD的发展有关。ROS催化的脂质过氧化产生双功能 亲电体（BFEs）。我们已经证明，由氧化应激产生的BFEs加速了 寡聚化，产生具有类似神经毒性和免疫反应性的寡聚体， 淀粉样蛋白衍生的可扩散配体。它们抑制蛋白酶体活性，导致线粒体 功能障碍，并促进T细胞的树突状细胞活化。重要的是，我们已经证明， AD患者死后海马中蛋白质上的BFE加合物水平显著升高 人的大脑，并与CERAD斑块评分和Braak阶段呈正相关。 我们发现2-羟基苄胺（2-HOBA）与BFEs的反应速度快1，600倍 而不是赖氨酸，阻止了体外和体内的蛋白质修饰。重要的是，在hApoE 4中， 在转基因小鼠中，2-HOBA抑制上述BFEs的所有作用，并阻止其工作。 记忆缺失 2-HOBA，一种存在于荞麦种子中的天然产物，已经被开发用于 Metabolic Technologies，Inc. (MTI，艾姆斯，IA）。化学、制造和 已经生成了对照数据，并且临床前药理学和毒理学数据 目前正在收集。在这个项目中，我们建议进行单次和多次递增剂量 需要进行表征2-HOBA的药代动力学、代谢和安全性的研究。我们 我还建议建立2-HOBA的脑转移率，并确定它是否减少 血液和脑脊液蛋白质氧化修饰标志物。

Approximately 5.2 million Americans are affected by Alzheimer’s disease (AD), and up to 13 million will be affected by 2050. At present, there is no preventive or curative treatment for AD or in age-related cognitive decline and clinical trials of cognitive-modifying compounds have not succeeded in identifying an effective treatment. Despite a lot of efforts, no candidates are available to slow down the development or even cure this devastating disease. Although most of the efforts are focusing on the amyloid and the tau pathways, we have taken a different approach and targeted oxidative stress. Oxidative stress is a major pathogenic mechanism that underlies both the pre-clinical development and subsequent progression of AD, and one that could potentially be targeted preventively as well as therapeutically. Levels of reactive oxygen species (ROS) increase during inflammation, mitochondrial dysfunction, and metal redox cycling catalyzed by A, all processes associated with AD development. ROS-catalyzed lipid peroxidation generates bifunctional electrophiles (BFEs). We have shown that BFEs generated by oxidative stress accelerate Aß oligomerization, generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid-derived diffusible ligands. They inhibit proteosomal activity, cause mitochondrial dysfunction, and promote dendritic cell activation of T cells. Importantly, we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains, and correlate positively with both the CERAD plaque score and the Braak stage. We have found that 2-hydroxybenzylamine (2-HOBA) reacts 1,600-fold faster with BFEs than lysine, preventing protein modification in vitro and in vivo. Importantly, in hApoE4 transgenic mice, 2-HOBA inhibits all the effects of BFEs described above, and prevents working memory deficit. 2-HOBA, a natural product present in buckwheat seeds, has been developed for use in humans by Metabolic Technologies, Inc. (MTI, Ames, IA). The chemical, manufacturing and control data have been generated and pre-clinical pharmacology and toxicology data are currently being collected. In this project, we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics, metabolism, and safety of 2-HOBA. We also propose to establish brain penetrance of 2-HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins.