Brain Shuttle Neprilysin reduces central Amyloid-β levels

Reducing Amyloid beta (A beta) in the brain is of fundamental importance for advancing the therapeutics for Alzheimer's disease. The endogenous metallopeptidase neprilysin (NEP) has been identified as one of the key A beta-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central A beta. We fused the extracellular catalytic domain of NEP to an active or inactive BS module. The two BS-NEP constructs were used to investigate the pharmacokinetic/pharmacodynamics relationships in the blood and the cerebrospinal fluid (CSF) in dose-response and multiple dosing. As previously shown, NEP was highly effective at degrading A beta in blood but not in the CSF compartment after systemic administration. In contrast, the NEP with an active BS module led to a significant CSF exposure of BS-NEP, followed by substantial A beta reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an A beta degrading enzyme across the blood-brain barriers to efficiently reduce A beta levels in both CSF and brain.