Enzymatic degradation contributes to the control of intracerebral amyloid-β (Aβ) 
peptide levels. Previous studies have demonstrated the therapeutic potential of 
viral vector-mediated neprilysin (NEP) gene therapy in mouse models of 
Alzheimer's disease (AD). However, clinical translation of NEP gene therapy is 
limited by ethical and practical considerations. In this study we have assessed 
the potential of convection-enhanced delivery (CED) as a means of elevating 
intracerebral NEP level and activity and degrading endogenous Aβ. We analyzed 
the interstitial and perivascular distribution of NEP following CED into rat 
striatum. We measured NEP protein level, clearance, activity, and toxicity by 
ELISA for NEP and synaptophysin, NEP-specific activity assay, and 
immunohistochemistry for NEP, NeuN, glial fibrillary acidic protein and Iba1. We 
subsequently performed CED of NEP in normal aged rats and measured endogenous Aβ 
by ELISA. CED resulted in widespread distribution of NEP, and a 20-fold 
elevation of NEP protein level with preservation of enzyme activity and without 
evidence of toxicity. CED in normal, aged rats resulted in a significant 
reduction in endogenous Aβ(40) (p = 0.04), despite rapid NEP clearance from the 
brain (half-life ~3 h). CED of NEP has therapeutic potential as a dynamically 
controllable Aβ(40)-degrading therapeutic strategy for AD. Further studies are 
required to determine the longer term effects on Aβ (including Aβ(42)) and on 
cognitive function.