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Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice

Iwata, N and Sekiguchi, M and Hattori, Y and Takahashi, A and Asai, M and Ji, B and Higuchi, M and Staufenbiel, M and Muramatsu, S and Saido, TC (2013) Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice. Scientific Reports.

Abstract

Accumulation of amyloid-beta peptide (A beta) 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 decreaseA beta 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 A beta 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 A beta 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

Item Type: Article
Additional Information: pubid: 105 nvp_institute: NIBR contributor_address: [Iwata, Nobuhisa; Sekiguchi, Misaki; Saido, Takaomi C.] RIKEN, Brain Sci Inst, Lab Proteolyt Neurosci, Wako, Saitama 3510198, Japan. [Iwata, Nobuhisa; Hattori, Yoshino; Takahashi, Akane; Asai, Masashi] Nagasaki Univ, Grad Sch Biomed Sci, Dept Mol Med Sci, Lab Mol Biol & Biotechnol, Nagasaki 8528521, Japan. [Ji, Bin; Higuchi, Makoto] Natl Inst Radiol Sci, Mol Imaging Ctr, Inage Ku, Chiba 2638555, Japan. [Staufenbiel, Matthias] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. [Muramatsu, Shin-ichi] Jichi Med Univ, Dept Med, Div Neurol, Shimotsuke, Tochigi 3290498, Japan.
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21943

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