Circulating neprilysin clears brain amyloid

• Published in: Molecular and cellular neuroscience 2010-10, Vol.45 (2), p.101-107
• Main Authors: Liu, Yinxing, Studzinski, Christa, Beckett, Tina, Murphy, M. Paul, Klein, Ronald L., Hersh, Louis B.
• Format: Article
• Language: English
• Subjects: Adeno-associated virus; Alzheimer's disease; Amyloid beta peptide; Amyloid beta-Peptides - metabolism; Animals; Blood Pressure; Blood-Brain Barrier - enzymology; Bradykinin - blood; Brain - metabolism; Brain Chemistry; Dependovirus; Gene therapy; Humans; Mice; Neprilysin; Neprilysin - blood; Neprilysin - genetics; Substance P - blood
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2010.05.014

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 Aβ. Soluble NEP expression in plasma was sustained over the 3-month time period it was measured. Secreted NEP decreased plasma Aβ by 30%, soluble brain Aβ by ∼ 28%, insoluble brain Aβ by ∼ 55%, and Aβ 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 Aβ was due to plasma NEP which altered blood-brain Aβ transport dynamics. Expressing NEP in plasma provides a convenient way to monitor enzyme activity during the course of its therapeutic testing.