Abstract 245: Intravenously Injected Human Apolipoprotein A-I Rapidly Enters the Central Nervous System via the Choroid Plexus in Mice
Background: Lipoprotein metabolism in the brain is based on particles that resemble high-density lipoproteins (HDL) that use apolipoprotein (apo) E as opposed to apoA-I as their primary protein component. Although apoA-I is not synthesized by astrocytes or microglia, which secrete apoE, it is abundant in cerebrospinal fluid (CSF) and is readily detectable in brain tissue lysates.However, the mechanisms by which plasma apoA-I enters and is metabolized within the central nervous system (CNS) are unknown.
Methods and Results: Western blot analysis shows that steady state levels of endogenous apoA-I in CSF and brain are approximately 0.01% and 10-15% of its levels in plasma and liver, respectively. Recombinant, fluorescently tagged, lipid-free human (h) apoA-I injected into the tail vein of wild-type mice localizes to the choroid plexus within 0.5h and accumulates in a saturable, dose-dependent manner in brain. hApoA-I accumulates in the brain for up to 2h, after which it is turned over with a half life of ~133 minutes, 3 times longer than the relatively quick turnover 40-45 minutes found in plasma, liver, and kidney. In vitro, hApoA-I is taken up and actively transported across confluent monolayers of primary human choroid epithelial cells.
Conclusions: Following intravenous injection, hApoA-I rapidly and strongly localizes to the choroid plexus, suggesting it gains access to the CNS primarily via the blood CSF barrier. Further, apoA-I found in the CNS of mice is exclusively derived from the circulation as apoA-I mRNA is not detectable in murine brain. These results suggest that apoA-I based HDL may primarily play a role in CSF lipoprotein metabolism in addition to potentially impacting cerebrovasculature health and function from the lumen of the vessel.
Author Disclosures: S. Stukas: None. J. Robert: None. M. Lee: None. I. Kulic: None. N. DeValle: None. M. Carr: None. J. Fan: None. D. Namjoshi: None. K. Lemke: None. M.N. Oda: None. C.L. Wellington: None.
- © 2014 by American Heart Association, Inc.