Histone Methylation, Energy Metabolism, and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an insidious, progressive, and irreversible neurodegenerative disease characterized by the deposition of extracellular amyloid β-protein (Aβ) to form senile plaques and abnormal phosphorylation of intracellular tau protein to form neuronal fiber tangles. The pathogenesis of AD is complex, and there are several hypotheses, primarily including the Aβ cascade hypothesis, the neurofibrillary tangle hypothesis, the inflammatory hypothesis, and the cholinergic hypothesis. It has been suggested that the dysregulation of multiple energy metabolic pathways, especially mitochondria metabolism, may be related to the severity of AD pathology and disease symptoms in the brain. The modification of histone (lysine) methylation, an actively regulated and reversible process, is closely related to energy metabolism and plays a crucial role in AD development. In summary, histone methylation, energy metabolism, and AD restricted and regulated each other. Here, we review the advances in the correlation between histone methylation, energy metabolism, and AD. This can provide further insights into the mechanisms underlying AD pathogenesis and its control.

Figure 1.

Histone methylation and demethylation process. Note: Histone methylation refers to the transfer of methyl groups to the lysine residues of histones catalyzed by KMTs, with SAM as the methyl donor, whereas SAM itself becomes SAH. Histone demethylation refers to the change of histone modification with α-KG as the substrate and the removal of methyl groups from the lysine residues catalyzed by KDMs, while α-KG becomes succinate. SAM: s-adenosyl-L-methionine; SAH: s-adenosyl-L-homocysteine; α-KG: α-ketoglutarate; Me: methyl.

Figure 2.

Glucose, fatty acid, and amino acid metabolism and TCA cycle. Note: ACO2: aconitase 2; IDH3A: isocitrate dehydrogenase 3A; α-KG: α-ketoglutaric acid; OGDH: α-ketoglutarate dehydrogenase; SUCLG2: succinyl- CoA synthetase; SDH: succinate dehydrogenase; FH: fumarate hydratase; MDH2: malate dehydrogenase 2; OAA: oxaloacetic acid; CS: citrate synthase; Glu: glutamate; Gln: glutamine; GLUD: glutamate dehydrogenase; GLS/GLS2: glutaminase; GSH: glutathione; GAD: glutamic acid decarboxylase; GABA-T: γ-aminobutyric acid transaminase; GABA: γ-aminobutyric acid; SSA: succinic semialdehyde; SSADH: succinate semialdehyde dehydrogenase

Figure 3.

The relationship and regulatory mechanisms of histone methylation, energy metabolism, and AD. Note: The content not reported in AD is marked in red.