Abstract
Reducing Amyloid β (Aβ) 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 Aβ-degrading enzymes. Delivery of NEP to the brain by utilizing the Brain Shuttle (BS) transport system offers a promising approach for clearing central Aβ. 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 Aβ 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 Aβ reduction in CSF and brain parenchyma. Our data show that a BS module against the transferrin receptor facilitates the transport of an Aβ degrading enzyme across the blood-brain barriers to efficiently reduce Aβ levels in both CSF and brain.
Highlights
The incidence of Alzheimer‘s disease (AD), the most common cause of dementia, rises dramatically with age[1]
The recombinant fusion proteins were generated by fusing a one–armed OX26 anti-rat transferrin receptor (TfR) antibody or a one-armed antibody directed against an irrelevant antigen to the extracellular catalytic domain of human NEP (hNEP) (Fig 1A)
NEP is an enzyme that breaks down the Amyloid β (Aβ) peptide[13], which forms amyloid plaques in the brain and has received much attention as a viable target for AD[14]
Summary
The incidence of Alzheimer‘s disease (AD), the most common cause of dementia, rises dramatically with age[1]. The accumulation of neuro-toxic β-amyloid (Aβ) species in the brain is believed to contribute to the pathology of AD. Aβ is produced through the cleavage of the amyloid precursor protein to release primarily soluble Aβ monomers (Aβ40 and Aβ42)[2]. Aβ accumulation could either be due to increased production or decreased clearance of Aβ and therapies are being developed to tackle both mechanisms in AD patients[3]. The challenge to bring clinically successful therapeutics to the market for the treatment of AD has been an intensive but unfulfilled pursuit for almost three decades[4]. Enzymatic degradation of Aβ monomers has received attention over the past decade. Among the identified enzymes capable of degrading Aβ into less neuro-toxic fragments, Neprilysin (NEP) appears to have the greatest potential to effectively degrade toxic Aβ species[5].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
