title: Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice.
abstract: Accumulation of amyloid-β peptide (Aβ) in the brain is closely associated with cognitive decline in Alzheimer's disease (AD). Stereotaxic infusion of neprilysin-encoding viral vectors into the hippocampus has been shown to decrease Aβ in AD-model mice, but more efficient and global delivery is necessary to treat the broadly distributed burden in AD. Here we developed an adeno-associated virus (AAV) vector capable of providing neuronal gene expression throughout the brains after peripheral administration. A single intracardiac administration of the vector carrying neprilysin gene in AD-model mice elevated neprilysin activity broadly in the brain, and reduced Aβ oligomers, with concurrent alleviation of abnormal learning and memory function and improvement of amyloid burden. The exogenous neprilysin was localized mainly in endosomes, thereby effectively excluding Aβ oligomers from the brain. AAV vector-mediated gene transfer may provide a therapeutic strategy for neurodegenerative diseases, where global transduction of a therapeutic gene into the brain is necessary.
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. iwata-n@nagasaki-u.ac.jp
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Misaki
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Hattori
authors.forename: Akane
authors.initials: A
authors.lastname: Takahashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006624:Hippocampus; D007275:Injections, Intravenous; D051379:Mice; D015260:Neprilysin / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D015260:Neprilysin