title: Intracranial injection of AAV expressing NEP but not IDE reduces amyloid pathology in APP+PS1 transgenic mice.
abstract: The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor in Alzheimer's disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading enzyme (IDE), have been shown to cleave β-amyloid peptides (Aβ). We have previously reported reductions in amyloid in APP+PS1 mice with increased expression of ECE. In this study we compared the vector-induced increased expression of NEP and IDE. We used recombinant adeno-associated viral vectors expressing either native forms of NEP (NEP-n) or IDE (IDE-n), or engineered secreted forms of NEP (NEP-s) or IDE (IDE-s). In a six-week study, immunohistochemistry staining for total Aβ was significantly decreased in animals receiving the NEP-n and NEP-s but not for IDE-n or IDE-s in either the hippocampus or cortex. Congo red staining followed a similar trend revealing significant decreases in the hippocampus and the cortex for NEP-n and NEP-s treatment groups. Our results indicate that while rAAV-IDE does not have the same therapeutic potential as rAAV-NEP, rAAV-NEP-s and NEP-n are effective at reducing amyloid loads, and both of these vectors continue to have significant effects nine months post-injection. As such, they may be considered reasonable candidates for gene therapy trials in AD.
authors.affiliation: University of South Florida College of Medicine, Byrd Alzheimer's Institute, Department of Molecular Pharmacology and Physiology, Tampa, Florida, United States of America.
authors.forename: Nikisha
authors.initials: N
authors.lastname: Carty
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Nash
authors.forename: Milene
authors.initials: M
authors.lastname: Brownlow
authors.forename: Dana
authors.initials: D
authors.lastname: Cruite
authors.forename: Donna
authors.initials: D
authors.lastname: Wilcock
authors.forename: Maj-Linda B
authors.initials: ML
authors.lastname: Selenica
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lee
authors.forename: Marcia N
authors.initials: MN
authors.lastname: Gordon
authors.forename: Dave
authors.initials: D
authors.lastname: Morgan
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005625:Frontal Lobe / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007267:Injections; D007339:Insulysin / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*; D012886:Skull
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D015260:Neprilysin; D007339:Insulysin
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