title: Convection-enhanced delivery of neprilysin: a novel amyloid-β-degrading therapeutic strategy.
abstract: 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.
authors: Functional Neurosurgery Research Group, University of Bristol, Bristol, UK.
authors: Neil U
authors: NU
authors: Barua
authors: J Scott
authors: JS
authors: Miners
authors: Alison S
authors: AS
authors: Bienemann
authors: Marcella J
authors: MJ
authors: Wyatt
authors: Katharina
authors: K
authors: Welser
authors: Alethea B
authors: AB
authors: Tabor
authors: Helen C
authors: HC
authors: Hailes
authors: Seth
authors: S
authors: Love
authors: Steven S
authors: SS
authors: Gill
mesh_terms: D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002404:Catheterization; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D015260:Neprilysin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D059906:Neuroimaging; D009553:Nimodipine / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D016229:Amyloid beta-Peptides; D034961:Antigens, Nuclear; D002121:Calcium Channel Blockers; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D014677:Pharmaceutical Vehicles; C546339:Rbfox3 protein, rat; D016708:Synaptophysin; D011092:Polyethylene Glycols; D009553:Nimodipine; D015260:Neprilysin