Acetylation of the microtubule-associated protein tau promotes its polymerization into neurofibrillary tangles that are implicated in the pathology of Alzheimer’s disease (AD). The gaseous neurotransmitter nitric oxide (NO) regulates cell signaling through the nitrosylation of proteins. We found that NO production and tau acetylation at Lys²⁸⁰ occurred in the brain tissue in mice and in cultured mouse cortical neurons in response to exposure to amyloid-β_1–42 (Aβ_1–42), a peptide that is also implicated in AD. An increased abundance of NO facilitated the S-nitrosylation (SNO) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). S-nitrosylated GAPDH (GAPDH-SNO) promoted the acetylation and activation of the acetyltransferase p300 and facilitated the nitrosylation and inactivation of the deacetylase sirtuin 1 (SIRT1). The abundance of GAPDH-SNO was increased in postmortem brain samples from AD patients. Preventing the increase in GAPDH-SNO abundance in both cultured neurons and mice, either by overexpression of the nitrosylation mutant of GAPDH (GAPDH C150S) or by treatment with the GAPDH nitrosylation inhibitor CGP3466B (also known as omigapil), abrogated Aβ_1–42–induced tau acetylation, memory impairment, and locomotor dysfunction in mice, suggesting that this drug might be repurposed to treat patients with AD.

微管相关蛋白tau的乙酰化促进其聚合成神经原纤维缠结，这与阿尔茨海默氏病（AD）的病理学有关。气态神经递质一氧化氮（NO）通过蛋白质的亚硝基化调节细胞信号传导。我们发现，暴露于淀粉样蛋白_β1–42（_Aβ1–42）（也与AD有关的一种肽）后，小鼠的大脑组织和培养的小鼠皮质神经元中均未在Lys ²⁸⁰处产生NO生成和tau乙酰化。。NO含量的增加促进了3-磷酸​​甘油醛脱氢酶（GAPDH）的S-亚硝基化（SNO）。小号-亚硝基化的GAPDH（GAPDH-SNO）促进了乙酰基转移酶p300的乙酰化和活化，并促进了脱乙酰基酶沉默调节蛋白1（SIRT1）的亚硝基化和失活。AD患者的死后脑样本中GAPDH-SNO的含量增加。通过过表达GAPDH的亚硝化突变体（GAPDH C150S）或通过用GAPDH亚硝化抑制剂CGP3466B（也称为omigapil）处理，消除_Aβ1–42 –来防止培养的神经元和小鼠中GAPDH-SNO丰度的增加。诱导小鼠的tau乙酰化，记忆力减退和运动功能障碍，表明该药物可能被重新用于治疗AD患者。