Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, 
is the most common form of dementia. Therapeutic options have been elusive due 
to the inability to deliver proteins across the blood-brain barrier (BBB). In 
order to improve the therapeutic potential for AD, we utilized a promising new 
approach for delivery of proteins across the BBB. We generated a lentivirus 
vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB 
transport domain and delivered this by intra-peritoneal injection to amyloid 
protein precursor (APP) transgenic model of AD. Treated mice had reduced levels 
of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, 
mice treated with the neprilysin targeting the CNS had a reversal of memory 
deficits. Thus, the addition of the ApoB transport domain to the secreted 
neprilysin generated a non-invasive therapeutic approach that may be a potential 
treatment in patients with AD.