Apolipoprotein A-I in mouse cerebrospinal fluid derives from the liver and intestine via plasma high-density lipoproteins assembled by ABCA1 and LCAT.

Abstract

Apolipoprotein (apo) A-I, the major structural protein of high-density lipoprotein (HDL), is present in human and mouse cerebrospinal fluid (CSF) despite its lack of expression in brain cells. To identify the origin of apoA-I in CSF, we generated intestine-specific and liver-specific Apoa1 knockout mice (Apoa1^ΔInt and Apoa1^Δliv mice, respectively). Lipoprotein profiles of Apoa1^ΔInt and Apoa1^ΔLiv mice resembled those of control littermates, whereas knockout of Apoa1 in both intestine and liver (Apoa1^ΔIntΔLiv ) resulted in a 60-percent decrease in HDL-cholesterol levels, thus strongly mimicking the Apoa1^-/- mice. Immunoassays revealed that mouse apoA-I was not present in the CSF of the Apoa1^ΔIntΔLiv mice. Furthermore, apoA-I levels in CSF were highly correlated with plasma spherical HDL levels, which were regulated by ABCA1 and LCAT. Collectively, these results suggest that apoA-I protein in CSF originates in liver and small intestine and is taken up from the plasma.