Fig. 3

Brain cholesterol homeostasis is to a lesser extent related to peripheral tissues, as separated by the BBB barrier. The main pathways for cholesterol synthesis in the brain are the Bloch pathway in astrocytes, where cholesterol is derived from desmosterol, and to a lesser extent the Kandutsch-Russell pathway in neurons, where cholesterol is derived from 7-dehydrocholesterol. The synthesis process that is regulated by the sterol regulatory element-binding protein 2 (SREBP-2). In astrocytes, cholesterol binds to ApoE to form lipoproteins that are secreted into the extracellular fluid via ABC transporter proteins (especially ABCA1) and finally taken up and transported to neurons, microglia, and oligodendrocytes by the two types of LDL receptors, low density lipoprotein receptor (LDLR) and low-density lipoprotein receptor-related protein (LRP). ApoE is recycled after receptor-mediated endocytosis. Cholesterol is used for energy supply, normal production of inflammation-related signals and myelin formation. To maintain cholesterol homeostasis, excess cholesterol is esterified by enzyme acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1/SOAT1) in the andoplasmic reticulum and stored as cholesterol ester (CE) in LDs. The cholesterol associated with peripheral tissues by the brain is 24-hydroxycholesterol (24S-OH) and 27-hydroxycholesterol (27-OH). The neuron-specific enzyme 24-hydroxylase (CYP46A1) converts excess cholesterol to the more hydrophilic metabolite 24S-OH, which either diffuses into the somatic circulation via the BBB or acts as a A natural endogenous agonist of liver X receptor (LXR) controls cholesterol homeostasis. 27-OH is produced mainly in peripheral tissues by the catalytic activity of CYP 27 A1, which diffuses from the circulation to the brain via the BBB and is involved in microglia homeostasis. To a lesser extent, brain cholesterol is also oxidised to 27-OH by sterol 27-hydroxylase (CYP27A1), which is then oxidised by enzyme oxysterol 7-alpha-hydroxylase (CYP7B1) to 7α-hydroxy-3-oxo-4-cholestenoic acid (7-OH-4-C), which is cleared in the liver after passing through the BBB