Neuroinflammation Induces Myelin Damage by Inhibiting Gapdh of Oligodendrocytes in the Hippocampus

Abstract

Background Myelin damage has been detected in central nervous system disease accompanied by neuroinflammation and cognitive dysfunction. However, the mechanism of myelin damage associated with neuroinflammation in the aged brain has not been clarified. Methods We explored the mechanism of myelin damage induced by neuroinflammation in the hippocampus of aged rats through both in vivo and in vitro approaches from the perspective of energy synthesis in oligodendrocytes. We developed a neuroinflammation model by single intraperitoneal injection of LPS and determined cognitive dysfunction and myelin damage in the hippocampus. Single-cell RNA sequencing was employed to exam gene expression changes related to neuroinflammation in oligodendrocytes of the hippocampus and identified Gapdh as a significantly downregulated gene. In vitro, OLN-93 cells were induced to differentiate into mature oligodendrocytes and treated with TNF-α. The effect of Gapdh on TNF-α-induced energy synthesis suppression and MBP reduction in mature oligodendrocytes, and mitochondrial damage, was assessed through Gapdhoverexpression. Results In aged rats, spatial learning and memory impairments were triggered by LPS, alongside neuroinflammatory responses, as evidenced by elevated levels of TNF-α and IL-1β in the hippocampus. Additionally, there was a reduction in myelin protein expression and disorganization within the myelin structure, which was notably thinner in the hippocampus of the LPS-treated group. The proportion of mature oligodendrocyte clusters related to myelination and remyelination decreased, and the expression level of Gapdh significantly decreased in each oligodendrocyte cluster of the LPS group. In vitro, TNF-α induced mature oligodendrocyte apoptosis and reduced GAPDH and MBP expression. The glycolysis and oxidative phosphorylation ability of cells decreased, accompanied by decreased lactate concentration and ATP content. Mitochondrial oxidative stress and damage were also detected. Overexpression of Gapdh improved damage induced by TNF-α. Conclusions Neuroinflammation impairs the energy synthesis functions of glycolysis and oxidative phosphorylation, and mitochondria in mature oligodendrocytes, by inhibiting Gapdh expression. Lack of energy support decreases myelin basic protein levels, subsequently resulting in myelin deterioration, which may lead to cognitive dysfunction.