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

Article type: Research Article

Authors: Sharman, Matthew J.^{a; b; c; d} | Morici, Michael^{c; d} | Hone, Eugene^{c; d} | Berger, Tamar^{c; d} | Taddei, Kevin^{b; c; d} | Martins, Ian J.^{a; b; c; d} | Lim, Wei Ling F.^{c; d} | Singh, Sajla^{b; c} | Wenk, Markus R.^{e; f} | Ghiso, Jorge^g | Buxbaum, Joseph D.^h | Gandy, Sam^g | Martins, Ralph N.^{a; b; c; d; *}

Affiliations: [a] Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia | [b] School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia | [c] McCusker Foundation for Alzheimer's Disease Research Inc, Hollywood Private Hospital, Nedlands, WA, Australia | [d] School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, WA, Australia | [e] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [f] Biological Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [g] Department of Pathology, New York University School of Medicine, New York, NY, USA | [h] Mount Sinai School of Medicine, New York, NY, USA

Correspondence: [*] Correspondence to: Prof. Ralph Martins, Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Western Australia 6027, Australia. Tel.: +61 8 63045456; E-mail: r.martins@ecu.edu.au.

Abstract: The ε4 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 ε2, ε3, and ε4 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 ε4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Aβ42 over time compared to APOE ε2/APOE knock-out rE2 and APOE ε3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Aβ42 is significantly altered by APOE genotype. Given that APOE ε4 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.

Keywords: Alzheimer's disease, amyloid-β, APOE genotype, peripheral sink hypothesis

DOI: 10.3233/JAD-2010-100141

Journal: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 403-409, 2010