Zhang Xiaoyu, Liu Yan, Rekowski Michaella J, Wang Ning
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Institute of Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, Kansas, USA.
Alzheimers Dement. 2025 Feb;21(2):e14481. doi: 10.1002/alz.14481. Epub 2024 Dec 30.
Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation.
We analyzed lactylation of tau in control and AD brain tissue and conducted cell-based assays. In addition, we used in vitro assays to determine whether p300 catalyzed tau lactylation.
Quantitative proteomics detected that tau lactylation was elevated in AD brains, with K residue at position 331 (K331) being a prominent site. Lactate induced tau lactylation, which increased tau phosphorylation and cleavage and reduced ubiquitination. Inhibition of lactate production lowered tau lactylation; p300 catalyzed tau lactylation.
Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target.
Elevated tau lactylation, particularly at K331, is evident in in human AD brain samples. Lactate induces tau lactylation, enhancing phosphorylation and cleavage while inhibiting ubiquitination. The acetyl-transferase p300 catalyzes tau lactylation, with K331 being the most prominent site.
高磷酸化tau蛋白的聚集（tau蛋白病）与阿尔茨海默病（AD）患者的认知障碍有关。在AD中，由于瓦伯格效应导致的代谢转变会使乳酸生成增加。乳酸可诱导蛋白质发生翻译后修饰（PTM），将乳酰基与赖氨酸（K）残基结合，这一过程称为乳酰化。
我们分析了对照脑组织和AD脑组织中tau蛋白的乳酰化情况，并进行了基于细胞的实验。此外，我们使用体外实验来确定p300是否催化tau蛋白的乳酰化。
定量蛋白质组学检测发现，AD脑内tau蛋白的乳酰化水平升高，331位的赖氨酸残基（K331）是一个主要位点。乳酸诱导tau蛋白乳酰化，增加了tau蛋白的磷酸化和裂解，并减少了泛素化。抑制乳酸生成可降低tau蛋白的乳酰化；p300催化tau蛋白的乳酰化。
我们的研究结果表明，tau蛋白乳酰化将代谢失调与tau蛋白病联系起来，可能成为一个新的诊断和治疗靶点。
在人类AD脑样本中，tau蛋白的乳酰化水平升高，尤其是在K331位点。乳酸诱导tau蛋白乳酰化，增强磷酸化和裂解，同时抑制泛素化。乙酰转移酶p300催化tau蛋白的乳酰化，K331是最主要的位点。
