Lactylation of tau in human Alzheimer's disease brains
Xiaoyu Zhang, Yan Liu, Michaella J. Rekowski, Ning Wang
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target. HIGHLIGHTS: 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.