Recently, a novel approach was developed for delivering therapeutic proteins to neurons of the CNS by targeting passage across the BBB. Fusion of the Apolipoprotein B (ApoB) low-density lipoprotein (LDL) receptor-binding domain to a targeted protein allows active transport of the protein across the BBB to the CNS. The fusion proteins can be taken up by neurons and astrocytes across the whole brain. To investigate the potential therapeutic value of a secreted neprilysin (NEP) targeted to the CNS, the authors generated lentivirus vectors expressing either the wildtype NEP, a secreted form of the NEP or a secreted form of the NEP fused with the LDL-receptor binding domain of ApoB and injected them intra-peritoneally in an amyloid protein precursor (APP) transgenic (tg) model of AD-like pathology. Results showed that ApoBSecNEP was efficiently trafficked into the CNS and reduced levels of Aβ and synaptic alterations in the brains of mice. In addition, we observed improvements in learning and memory just 1 month after vector delivery. These results suggest a novel, and improved approach for delivery of an Aβ degrading enzyme and other neuroactive peptides to the CNS for treatment of AD.