Neuroinflammation blocks cholesterol supply to myelin, revealing a pathway in demyelinating disease

Researchers have identified a molecular pathway through which neuroinflammation blocks the supply of cholesterol to myelin, the sheath surrounding neurons in the brain, causing demyelinating disease.

On the 2nd (local time), a research team from Hangzhou Normal University reported in the international journal Cell Reports that neuroinflammation abnormally activates the Wnt signaling pathway in astrocytes, disrupting cholesterol homeostasis and myelin integrity.

The researchers found that inflammation increases expression of the SREBF2 protein in astrocytes through the Wnt signaling pathway, raising intracellular cholesterol levels while suppressing expression of APOE, which exports cholesterol from cells.

Oligodendrocytes, which produce myelin, have a limited capacity to synthesize cholesterol themselves and must obtain about 80% of the cholesterol they need from outside the cell. This cholesterol is supplied mainly by astrocytes.

According to the researchers, when astrocytes supply less cholesterol to other cells, expression of the oligodendrocyte transcription factor MYRF and myelin-related genes decreases, undermining myelin maintenance and structural integrity.

In experiments with genetically modified mice, the researchers said, drug-induced increases in APOE expression partially reversed impaired oligodendrocyte differentiation and reduced expression of myelin-related genes caused by activation of the Wnt pathway.

Neuroinflammation is a common feature of brain injury, stroke and several neurodegenerative diseases. Rich in cholesterol and phospholipids, myelin acts as insulation that speeds the transmission of electrical signals along neuronal axons.

Damage to myelin can disrupt nerve signal transmission and lead to neurological diseases such as multiple sclerosis and leukodystrophy.

The researchers said the study identifies a regulatory pathway linking neuroinflammation, the Wnt signaling pathway, cholesterol metabolism and myelin integrity, providing an important theoretical basis for understanding the molecular mechanisms of inflammation-related demyelinating diseases and developing future treatment strategies.