Affiliations: [a] The McCusker Foundation for Alzheimer's Disease Research, Department Psychiatry and Neurogenetics, The University of Western Australia, C/- Hollywood Private Hospital, Monash Avenue, Nedlands, Western Australia 6009 | [b] Department of Biomedical and Sports Science, Edith Cowan University, Joondalup Drive, Joondalup Western Australia 6027
Correspondence:
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Corresponding author: A/Prof. Ralph Martins, The Sir James McCusker Alzheimer's disease Research Unit, Department of Psychiatry, The University of Western Australia, C/- Hollywood Private Hospital, 115 Monash Avenue, Nedlands, Perth Western Australia 6009. Tel.: +61 8 9346 6703; Fax: +61 8 9346 6666; E-mail: rmartins@cyllene.uwa.edu.au.
Abstract: The relationship between amyloid-β protein (Aβ) metabolism and Alzheimer's disease is currently poorly understood. While it is well known that the generation of Aβ results from enzymatic cleavage of its parent molecule, the amyloid β protein precursor (AβPP), there is little information available regarding its in vivo clearance. The E4 isoform of apolipoprotein E (apoE) has been associated with poor clearance of Aβ under in vitro conditions. This is thought to be due to its poor ability to bind Aβ compared with the other common isoforms, apoE2 and apoE3. Although cell culture studies support the notion that Aβ clearance depends upon apoE isoform, validation of these findings requires Aβ clearance studies in vivo. In this study, we examined the clearance of Aβ in vivo from the periphery in mice that expressed apoE (C57BL/6J) or lacked apoE (APOE knockout). We measured the clearance of peripherally injected Aβ over time and additionally, the quantities sequestered by peripheral organs. Western blot analysis of the murine plasma indicated that the half-life of Aβ in the periphery was approximately 15 minutes. The livers of the C57BL/6J mice were found to have sequestered approximately 40% of the total injected Aβ at 90 minutes post-injection, whilst their kidneys contained 5% of the total injected Aβ. In contrast, the livers and kidneys of the APOE knockout animals were found to contain no detectable Aβ. These findings indicate that Aβ is rapidly removed from the plasma by murine peripheral tissues and the rate of its clearance is affected by apoE.
Keywords: Amyloid-β protein, mouse, clearance, Alzheimer's disease, periphery, apolipoprotein E
