title: Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease.
abstract: Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades the amyloid beta (Abeta) peptides believed to be involved in the etiology of Alzheimer disease (AD). The focus of this study was to develop a new and tractable therapeutic approach for treating AD using NEP gene therapy. We have introduced adeno-associated virus (AAV) expressing the mouse NEP gene into the hindlimb muscle of 6-month-old human amyloid precursor protein (hAPP) (3X-Tg-AD) mice, an age which correlates with early stage AD. Overexpression of NEP in muscle decreased brain soluble Abeta peptide levels by approximately 60% and decreased amyloid deposits by approximately 50%, with no apparent adverse effects. Expression of NEP on muscle did not affect the levels of a number of other physiological peptides known to be in vitro substrates. These findings demonstrate that peripheral expression of NEP and likely other peptidases represents an alternative to direct administration into brain and illustrates the potential for using NEP expression in muscle for the prevention and treatment of AD.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
authors.forename: Yinxing
authors.initials: Y
authors.lastname: Liu
authors.forename: Christa
authors.initials: C
authors.lastname: Studzinski
authors.forename: Tina
authors.initials: T
authors.lastname: Beckett
authors.forename: Hanjun
authors.initials: H
authors.lastname: Guan
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hersh
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015260:Neprilysin