Apolipoprotein E influences amyloid-beta clearance from the murine periphery

The relationship between amyloid-beta protein (A beta) metabolism and Alzheimer's disease is currently poorly understood. While it is well known that the generation of A beta results from enzymatic cleavage of its parent molecule, the amyloid beta protein precursor (A beta PP), there is little information available regarding its in vivo clearance. The E4 isoform of apolipoprotein E (apoE) has been associated with poor clearance of A beta under in vitro conditions. This is thought to be due to its poor ability to bind A beta compared with the other common isoforms, apoE2 and apoE3. Although cell culture studies support the notion that A beta clearance depends upon apoE isoform, validation of these findings requires A beta clearance studies in vivo. In this study, we examined the clearance of A beta in vivo from the periphery in mice that expressed apoE (C57BL/6J) or lacked apoE (APOE knockout). We measured the clearance of peripherally injected A beta over time and additionally, the quantities sequestered by peripheral organs. Western blot analysis of the murine plasma indicated that the half-life of A beta in the periphery was approximately 15 minutes. The livers of the C57BL/6J mice were found to have sequestered approximately 40% of the total injected A beta at 90 minutes post-injection, whilst their kidneys contained 5% of the total injected A beta. In contrast, the livers and kidneys of the APOE knockout animals were found to contain no detectable A beta. These findings indicate that A beta is rapidly removed from the plasma by murine peripheral tissues and the rate of its clearance is affected by apoE.