Circulating neprilysin clears brain amyloid

The use of the peptidase neprilysin (NEP) as a therapeutic for lowering brain amyloid burden is receiving increasing attention. We have previously demonstrated that peripheral expression of NEP on the surface of hindlimb muscle lowers brain amyloid burden in a transgenic mouse model of Alzheimer's disease. In this study we now show that using adeno-associated virus expressing a soluble secreted form of NEP (secNEP-AAV8), NEP secreted into plasma is effective in clearing brain A beta. Soluble NEP expression in plasma was sustained over the 3-month time period it was measured. Secreted NEP decreased plasma A beta by 30%, soluble brain A beta by similar to 28%, insoluble brain A beta by similar to 55%, and A beta oligomers by 12%. This secNEP did not change plasma levels of substance P or bradykinin, nor did it alter blood pressure. No NEP was detected in CSF, nor did the AAV virus produce brain expression of NEP. Thus the lowering of brain Aft was due to plasma NEP which altered blood-brain A beta transport dynamics. Expressing NEP in plasma provides a convenient way to monitor enzyme activity during the course of its therapeutic testing. (C) 2010 Elsevier Inc. All rights reserved.