Novel protein acylations in Alzheimer's disease: Molecular, mechanisms, biological significance, and diagnostic and therapeutic potentials.

BACKGROUND

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by complex pathogenesis including amyloid-β (Aβ), hyperphosphorylated tau mediated neurofibrillary tangles (NFTs), energy metabolism disorders, and neuroinflammation, imposing significant burdens on patients' families and society. Increasing evidence implicates epigenetic modifications, particularly novel protein acylations, encompassing endogenous energy metabolites- mediated lysine succinylation (Ksucc), propionylation (Kpr), malonylation (Kmal), crotonylation (Kcr), butyrylation (Kbu), 2-hydroxyisobutyrylation (Khib), β-hydroxybutyrylation (Kbhb), and glutarylation (Kglu), lactylation (Kla), alongside benzoylation (Kbz) mediated by sodium benzoate metabolites and isonicotinylation (Kinic) induced by isoniazid, playing a pivotal role in AD pathogenesis.

AIM OF REVIEW: To enhance the mechanistic understanding of novel acylations, this review systematically summarizes the molecular biological significance of novel protein acylations and their involvement in AD pathogenesis and improvement.

KEY SCIENTIFIC CONCEPTS OF REVIEW: Novel acylations exert profound effects on chromatin architecture, DNA accessibility, and transcriptional regulation. Moreover, they critically coordinate protein properties and functions including modulating protein degradation, protein stability, enzyme activity, protein-protein interaction, and subcellular localization. Dysregulation of specific novel acylations orchestrates key cellular processes such as neuroinflammation, metabolic dysfunction, and programmed cell death, thereby contributing to AD progression. This review systematically delineates the mechanistic foundations of novel acylation modifications and underscores their molecular significance. Furthermore, we comprehensively synthesize current knowledge on the involvement of these acylations in AD, offering novel perspectives for developing targeted preventive and therapeutic strategies.