title: APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice.
abstract: 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.
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sharman
authors.forename: Michael
authors.initials: M
authors.lastname: Morici
authors.forename: Eugene
authors.initials: E
authors.lastname: Hone
authors.forename: Tamar
authors.initials: T
authors.lastname: Berger
authors.forename: Kevin
authors.initials: K
authors.lastname: Taddei
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Martins
authors.forename: Wei Ling F
authors.initials: WL
authors.lastname: Lim
authors.forename: Sajla
authors.initials: S
authors.lastname: Singh
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
mesh_terms: 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
chemical_list: 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)