title: Neprilysin gene transfer reduces human amyloid pathology in transgenic mice.
abstract: The degenerative process of Alzheimer's disease is linked to a shift in the balance between amyloid-beta (Abeta) production, clearance, and degradation. Neprilysin has recently been implicated as a major extracellular Abeta degrading enzyme in the brain. However, there has been no direct demonstration that neprilysin antagonizes the deposition of amyloid-beta in vivo. To address this issue, a lentiviral vector expressing human neprilysin (Lenti-Nep) was tested in transgenic mouse models of amyloidosis. We show that unilateral intracerebral injection of Lenti-Nep reduced amyloid-beta deposits by half relative to the untreated side. Furthermore, Lenti-Nep ameliorated neurodegenerative alterations in the frontal cortex and hippocampus of these transgenic mice. These data further support a role for neprilysin in regulating cerebral amyloid deposition and suggest that gene transfer approaches might have potential for the development of alternative therapies for Alzheimer's disease.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Marr
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Atish
authors.initials: A
authors.lastname: Mukherjee
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kindy
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015260:Neprilysin