title: Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.
abstract: 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.
authors.affiliation: 1 MedImmune, Milstein Building, Granta Park, Cambridge, CB21 6GH, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Henderson
authors.forename: Christin
authors.initials: C
authors.lastname: Andersson
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narwal
authors.forename: Juliette
authors.initials: J
authors.lastname: Janson
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Goldschmidt
authors.forename: Paulina
authors.initials: P
authors.lastname: Appelkvist
authors.forename: Anna
authors.initials: A
authors.lastname: Bogstedt
authors.forename: Ann-Charlott
authors.initials: AC
authors.lastname: Steffen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Haupts
authors.forename: Jan
authors.initials: J
authors.lastname: Tebbe
authors.forename: Per Ola
authors.initials: PO
authors.lastname: Freskgård
authors.forename: Lutz
authors.initials: L
authors.lastname: Jermutus
authors.forename: Matthew
authors.initials: M
authors.lastname: Burrell
authors.forename: Susan B
authors.initials: SB
authors.lastname: Fowler
authors.forename: Carl I
authors.initials: CI
authors.lastname: Webster
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D015260:Neprilysin
keywords: Alzheimer’s disease; amyloid-β; neprilysin; peripheral sink hypothesis