Serum amyloid A transport across the blood-brain barrier increases with inflammation and is regulated by HDL

Abstract

Serum amyloid A (SAA) isoforms 1 and 2 are acute phase lipoproteins that are primarily produced by the liver. SAA in blood can increase dramatically during infection, and more modestly during low-grade, chronic systemic inflammation. Nearly all SAA in blood is bound to high-density lipoprotein (HDL). SAA may be an important mediator of neuroinflammation, as its overexpression in the liver causes increase in SAA in the brain, as well as gliosis and depressive-like behavior in mice. We hypothesized that SAA can access the CNS by crossing the blood-brain barrier (BBB), and that HDL modulates SAA transport across the BBB. We first characterized BBB transport kinetics of 125I-labeled SAA1 and 2. 125I-SAA2 crossed the mouse BBB 5x faster than 125I-SAA1, at a rate comparable to that of insulin. Both isoforms completely traversed the BBB and entered brain parenchyma, and transport of both isoforms was not saturable. Both isoforms also rapidly associated with HDL in blood. The transport rate of 125I-SAA2 increased 24 h after a 3 mg/kg injection of lipopolysaccharide independently of BBB disruption. Finally, HDL inhibited SAA transport across the BBB. Therefore, systemic inflammation could contribute to SAA accumulation in the CNS by increasing SAA concentrations in blood, and BBB transport. However, BBB transport of SAA may also be inhibited by HDL, either through HDL binding or competition with other HDL lipoproteins.