Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications

High-Density Lipoprotein (HDL) not only mediates reverse cholesterol transport in the periphery but also significantly influences Blood-Brain Barrier (BBB) function within the central nervous system by regulating lipid metabolism, inflammatory responses, oxidative stress, Aβ trans-barrier clearance, and endothelial nitric oxide signaling. Variations in structural composition and biological properties between plasma HDL and brain-derived HDL-like particles enable them to perform both synergistic and distinct roles in maintaining cholesterol homeostasis, protecting tight junctions, regulating barrier permeability, facilitating Aβ efflux, and stabilizing the neurovascular unit. Key components such as ApoA-I, the ApoM/Sphingosine-1-Phosphate (S1P) signaling axis, and ApoE preserve BBB integrity by enhancing endothelial and pericyte functions, stabilizing intercellular junctions, inhibiting matrix metalloproteinase activity, and reducing neuroinflammation. Additionally, HDL/HDL-like particles alleviate barrier stress by facilitating the clearance of metabolic waste through the glymphatic system. Existing research collectively suggests that HDL-like particles, as a multifaceted regulator of BBB homeostasis, play a crucial role in maintaining neurological health and influencing disease processes.