Establishing causality for protein lactylation in Alzheimer’s disease: site validation, evidence standards, and experimental priorities

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2026-11-01 Epub Date: 2026-08-10 DOI:10.1016/j.bcp.2026.118343

Sajid Ali, Asma Ayaz, Wajid Zaman

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引用次数: 0

Abstract

Protein lysine lactylation has emerged as a candidate interface between metabolic stress and Alzheimer’s disease (AD), but the strength of individual claims varies. This focused review evaluates whether reported histone and non-histone lactylation events meet analytical and experimental requirements for causal interpretation. Direct AD evidence is more robust for plaque-associated microglial histone H4 lysine 12 lactylation (H4K12la)–pyruvate kinase M2 (PKM2) feedback in an amyloid model. Histone H3 lysine 18 lactylation (H3K18la)–nuclear factor-κB (NF-κB) signaling is supported principally in senescent microglia and ageing or AD-related models. Human tau K331 lactylation demonstrates disease-associated occurrence but not quantitative occupancy, temporal precedence or residue-specific necessity. Amyloid precursor protein (APP) K612 lactylation provides a potentially protective mechanism supported by site-resolved identification, cellular perturbation and in vivo rescue. Histone H3 lysine 9 lactylation (H3K9la) and additional substrates remain hypothesis-generating. We distinguish putative enzymatic L-lactylation from methylglyoxal-derived D-lactoylation and define minimum standards for antibody specificity, stereochemistry, site localization, occupancy, protein abundance, cell composition, post-mortem quality, isotope tracing, genetic substitution and rescue. A four-tier framework separates extrapolated evidence, human occurrence or relevant in vivo association, site-specific AD-model mechanisms supported by intervention and rescue, and quantified, cell-resolved, residue-causal evidence independently replicated in human-relevant systems. Six experimental stages are proposed for advancing a candidate site from detection to human relevance. Current evidence supports protein lactylation as a context-dependent disease-modifying layer rather than a single upstream driver. Therapeutic development should prioritize validated sites and biomarker-defined cell states rather than indiscriminate suppression of lactate metabolism or global lactylation.

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建立阿尔茨海默病中蛋白质乳酸化的因果关系：现场验证，证据标准和实验重点。

蛋白质赖氨酸乳酸化已成为代谢应激和阿尔茨海默病（AD）之间的候选界面，但个人主张的强度各不相同。本综述评估了报道的组蛋白和非组蛋白乳酸化事件是否符合因果解释的分析和实验要求。在淀粉样蛋白模型中，斑块相关的小胶质组蛋白H4赖氨酸12乳酸化(H4K12la)-丙酮酸激酶M2 （PKM2）反馈的直接AD证据更为有力。组蛋白H3赖氨酸18乳酸化(H3K18la)-核因子-κB （NF-κB）信号主要在衰老小胶质细胞和衰老或ad相关模型中得到支持。人类tau K331乳酸化显示了与疾病相关的发生，但没有定量占据、时间优先或残留特异性必要性。淀粉样蛋白前体蛋白（APP） K612乳酸化提供了潜在的保护机制，支持位点分辨识别、细胞扰动和体内救援。组蛋白H3赖氨酸9乳酸化（H3K9la）和其他底物仍然是假设产生的。我们区分了假定的酶促l-乳酸化和甲基乙二醛衍生的d -乳酸化，并定义了抗体特异性、立体化学、位点定位、占用、蛋白质丰度、细胞组成、死后质量、同位素示踪、遗传替代和拯救的最低标准。一个四层框架将外推证据、人类发生或相关体内关联、干预和救援支持的特定位点ad模型机制，以及在人类相关系统中独立复制的量化、细胞解析、残留因果证据分开。提出了将候选位点从检测到人类相关性的六个实验阶段。目前的证据支持蛋白质乳酸化是一个依赖环境的疾病修饰层，而不是一个单一的上游驱动因素。治疗开发应优先考虑经过验证的位点和生物标志物定义的细胞状态，而不是不分青红皂白地抑制乳酸代谢或整体乳酸化。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.