Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)

项目总结 阿尔茨海默病(AD)和相关痴呆症(ADRD)是公认的主要公共卫生问题， 预计美国人口老龄化将进一步恶化--美国65岁及以上人口的数量将 到2050年达到8800万。然而，尽管作出了密集的努力，但仍缺乏足够有效的 治疗选择。晚期糖基化终产物(AGE)的形成是AD的一个公认的致病因素 进展，影响淀粉样β蛋白和tau蛋白。大脑中充满了葡萄糖和抗坏血酸，这两种物质 是年龄的前兆。糖基化终产物的形成是由蛋白质上的葡萄糖加合物通过氧化分解而开始的。 需要氧化还原金属离子催化的化学反应，众所周知，AD进展会导致大脑 促氧化剂铜和铁的积累。这些AGE促进剂会产生有毒的自由基和反应性 氧物种(ROS)可以独立地导致神经元损伤。我们的假设是，一名候选药物 即：(1)是脑渗透剂，(2)抑制AGE的形成，(3)减少氧化还原金属离子将表现出的氧化 治疗AD/ADRD的疗效观察我们在这个提案中提出了新的“Amadorin”候选药物PTG-630，a 晚期糖基化终产物(AGEs)的有效抑制剂，也具有作为抗氧化剂的双重潜力 与氧化还原金属离子，特别是Cu2+的结合有关。我们之前发现PTG-630可以预防轻微的 糖尿病大鼠和AD转基因小鼠模型在发病时开始治疗时的认知障碍 疾病的威胁。我们现在建议评估PTG-630在逆转已建立的认知方面的治疗潜力 多种AD动物模型中的功能障碍和神经变性，因为这是临床上最有可能的情况 使用治疗剂。

PROJECT SUMMARY Alzheimer’s Disease (AD) and related dementias (ADRD) are recognized as major public health issues that are projected to worsen in the aging U.S. population — the number of people of age 65 and older in the U.S. will reach 88 million by 2050. However, despite intensive efforts, there is an absence of sufficiently effective therapeutic options. Advanced glycation end products (AGE) formation is an established pathogenic factor in AD progression, impacting both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which are AGE precursors. AGE formation is initiated by the breakdown of glucose adducts on proteins via an oxidative chemical reaction requiring redox metal ion catalysis, and it is known that AD progression leads to brain accumulation of pro-oxidant copper and iron. These AGE accelerants generate toxic free radicals and reactive oxygen species (ROS) that can independently cause neuronal damage. Our hypothesis is that a drug candidate that: (1) is brain penetrant, (2) inhibits AGE formation, and (3) reduces oxidation by redox metal ions will exhibit efficacy in treating AD/ADRD. We advance in this proposal the novel “Amadorin” drug candidate PTG-630, a potent inhibitor of advanced glycation end products (AGEs) that also has the dual potential as an antioxidant due to its binding of redox metal ions, particularly Cu2+. We previously discovered that PTG-630 prevents mild cognitive impairment in diabetic rats and in a transgenic mouse model of AD when treatment was begun at onset of disease. We now propose to evaluate the therapeutic potential of PTG-630 in reversing established cognitive dysfunction and neurodegeneration in multiple animal models of AD, as this is the most likely scenario for clinical use of a therapeutic agent.