Fig. 1

Function and mechanism of various novel HPTMs in AD. Fatty acids, amino acids, glucose, ketones, and lactic acid generate various acyl-CoAs, which are substrates for various novel HPTMs. Lactic acid-induced H4K12la activates the transcription of glycolysis-related genes (including HIF-1A, PKM, and LDHA), thus exacerbating neuroinflammation in AD. NEAT1 changes the acylase activity of P300 by binding to P300 and increasing H3K27ac/H3K27cr, which downregulates endocytosis-related genes (CAV2, TGFB2, and TGFBR) and inhibits the uptake of Aβ in AD. KGDHC and su-CoA in mitochondria efflux into the cytoplasm, resulting in the upregulation of APP and tau succinylation, promoting Aβ accumulation, plaque formation, and tau aggregation into tangles. Kbhb, Kmal and Khib have been shown to be closely associated with AD; however, their exact mechanisms of action remain unclear. AD Alzheimer’s diseaseβ; LCFA, Long-chain fatty acid; SCFA, Short-chain fatty acid; TAC, Tricarboxylic acid cycle; FAO, Fatty acid oxidation; HIF-1A, Hypoxia-inducible factor-1A; PKM, Pyruvate kinase M; LDHA, Lactate dehydrogenase A; NEAT1, Nuclear paraspeckle assembly transcript 1; ACSS2, Acetyl-CoA synthetase; P300, An acetyltransferase; CBP CREB-binding protein; HDACs Histone deacetylases; SIRT, Sirtuin; APP, Amyloid Precursor Protein; CAV2, Caveolin 2; TGFB2, Transforming growth factor-beta 2; TGFBR, TGF-beta receptor; KGDHC, α-ketoglutarate dehydrogenase complex; su-CoA, Succinyl-CoA; ATP, Adenosine triphosphate; Kbhb, β-hydroxybutyrylation; Ksucc, succinylation; Khib, 2-hydroxyisobutyrylation; Kmal Malonylation