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Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β

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Simon J. Henderson, Christin Andersson, Rajesh Narwal, Juliette Janson, Tom J. Goldschmidt, Paulina Appelkvist, Anna Bogstedt, Ann-Charlott Steffen, Ulrich Haupts, Jan Tebbe, Per Ola Freskgård, Lutz Jermutus, Matthew Burrell, Susan B. Fowler, Carl I. Webster
DOI: http://dx.doi.org/10.1093/brain/awt308 553-564 First published online: 20 November 2013

Summary

Alzheimer’s disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-β in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-β are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby reducing formation of plaques predominantly composed of insoluble amyloid-β; the so-called peripheral sink hypothesis. Here we describe the use of an amyloid-β degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to albumin to extend plasma half-life and has been engineered to confer increased amyloid-β degradation activity. We used this molecule to investigate the effect of degradation of peripheral amyloid-β on amyloid-β levels in the brain and cerebrospinal fluid after repeated intravenous dosing for up to 4 months in Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved highly effective at degradation of amyloid-β in the periphery but did not alter brain or cerebrospinal fluid amyloid-β levels, suggesting that the peripheral sink hypothesis is not valid and is the first time that this has been demonstrated in non-human primates.

  • Alzheimer’s disease
  • peripheral sink hypothesis
  • amyloid-β
  • neprilysin
  • Abbreviations
    APP
    amyloid precursor protein
    HSA-hNepv
    human serum albumin-human neprilysin variant fusion protein
    MSA-mNEPv
    mouse serum albumin-mouse neprilysin variant fusion protein
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