APOE Genotype Results in Differential Effects on the Peripheral Clearance of Amyloid-β42 in APOE Knock-in and Knock-out Mice

The epsilon 4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-beta (A beta) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE(-/-) mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic A beta(42) in APOE epsilon 2, epsilon 3, and epsilon 4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear A beta(42) from their bloodstream. Both APOE epsilon 4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma A beta(42) over time compared to APOE epsilon 2/APOE knock-out rE2 and APOE epsilon 3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of A beta(42) is significantly altered by APOE genotype. Given that APOE epsilon 4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of A beta which may impact on clearance from the brain.