Enhanced Proteolytic Clearance of Plasma Aβ by Peripherally Administered Neprilysin Does Not Result in Reduced Levels of Brain Aβ in Mice

Accumulation of beta-amyloid (A beta) in the brain is believed to contribute to the pathology of Alzheimer's Disease (AD). A beta levels are controlled by the production of A beta from amyloid precursor protein, degradation by proteases, and peripheral clearance. In this study we sought to determine whether enhancing clearance of plasma A beta with a peripherally administered A beta-degrading protease would reduce brain A beta levels through a peripheral sink. Neprilysin (NEP) is a zinc-dependent metalloprotease that is one of the key A beta-degrading enzymes in the brain. We developed a NEP fusion protein with in vitro degradation of A beta and a 10 day plasma half-life in mouse. Intravenous administration of NEP to wild-type and APP23 transgenic mice resulted in dose-dependent clearance of plasma A beta. However, this did not correspond to reduced levels of soluble brain A beta with treatment up to 5 weeks in WT mice or formic acid-extractable brain A beta with 3 month treatment in aged APP23. In contrast, intracranial injection of NEP resulted in an acute decrease in soluble brain A beta. We found no change in amyloid precursor protein gene expression in mice treated with intravenous NEP, suggesting that the lack of effects in the brain following this route of administration was not caused by compensatory upregulation of A beta production. Taken together, these results suggest a lack of a robust peripheral A beta efflux sink through which brain amyloid burdens can be therapeutically reduced.