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.