APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice.
The epsilon4 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 (Abeta) 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 Abeta42 in APOE epsilon2, epsilon3, and epsilon4 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 Abeta42 from their bloodstream. Both APOE epsilon4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Abeta42 over time compared to APOE epsilon2/APOE knock-out rE2 and APOE epsilon3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Abeta42 is significantly altered by APOE genotype. Given that APOE epsilon4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Abeta which may impact on clearance from the brain.
Sharman
Matthew J
MJ
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia.
Morici
Michael
M
Hone
Eugene
E
Berger
Tamar
T
Taddei
Kevin
K
Martins
Ian J
IJ
Lim
Wei Ling F
WL
Singh
Sajla
S
Wenk
Markus R
MR
Ghiso
Jorge
J
Buxbaum
Joseph D
JD
Gandy
Sam
S
Martins
Ralph N
RN
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics* / Q000494:pharmacology; D053318:Apolipoprotein E3 / Q000235:genetics* / Q000494:pharmacology; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42)