Redox modifications are described that can be harnessed for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). The approach has shown potential therapeutic efficacy in AD in both transgenic mouse and hiPSC cerebral organoids models. In this review, two such redox targets are highlighted. First, protein S-nitrosylation of the NMDA-type of glutamate receptor is described as a potential therapeutic target. Second, an S-alkylation reaction of critical, redox-active cysteine thiol(s) on the protein KEAP1 to activate the anti-oxidant/anti-inflammatory transcription factor NRF2 is proposed. In both approaches, we utilize compounds described as pathologically activated therapeutics (or “PAT” drugs), which can only be activated by the disease process that they then combat. Thus, PAT drugs remain relatively innocuous and therefore clinically-tolerated in normal tissue in the absence of disease, thereby avoiding severe side effects both systemically and in the brain.

描述了氧化还原修饰，可用于治疗神经退行性疾病，包括阿尔茨海默氏病 (AD)。该方法在转基因小鼠和 hiPSC 大脑类器官模型中显示出潜在的 AD 治疗效果。在这篇评论中，突出了两个这样的氧化还原目标。首先，NMDA 型谷氨酸受体的蛋白质 S-亚硝基化被描述为潜在的治疗靶点。其次，提出了关键的氧化还原活性半胱氨酸硫醇对蛋白质 KEAP1 的 S-烷基化反应，以激活抗氧化/抗炎转录因子 NRF2。在这两种方法中，我们都使用被描述为病理激活疗法（或“PAT”药物）的化合物，这些化合物只能被它们随后对抗的疾病过程激活。因此，