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

The ℇ4 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-β (Aβ) 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 Aβ₄₂ in APOE ℇ2, ℇ3, and ℇ4 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 Aβ₄₂ from their bloodstream. Both APOE ℇ4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ₄₂ over time compared to APOE ℇ2/APOE knock-out rE2 and APOE ℇ3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ₄₂ is significantly altered by APOE genotype. Given that APOE ℇ4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Aβ which may impact on clearance from the brain. [ABSTRACT FROM AUTHOR]