Figure 3.

BA metabolism in the brain and its association with cognitive dysfunction-related diseases. In the brain, cholesterol is oxidized to 24-OH via CYP46A1. The 24-OH can easily exit the brain through the ABCA1. This is the main way of cholesterol clearance in the brain. ① In AD, the BBB is broken due to the hydrophobic environment created by an increase in blood lipids (hyperlipidemia and hypercholesterolemia), which allows toxins produced by the gut flora to penetrate the brain. Secondary BAs damage neurons that produce CYP46A1, simultaneously activating FXR and reducing the expression of CYP46A1. As a result, the cholesterol clearance pathway in the brain is disrupted, and the high-cholesterol environment in the brain positively regulates β- and γ-secretase expression, increasing the amyloid protein production pathway, leading to the deposition of Aβ in the brain. ② In addition, neuroinflammation caused by activation of microglia in HE is thought to be closely associated with the development of cognitive dysfunction. Specific conjugated BAs in the brain induce microglial activation and secrete proinflammatory factors by activating S1P2R. This process is not directly acted on microglia but through signal transduction communication between neurons and microglia, which is mediated by CCL2.