Brain Shuttle Neprilysin reduces central Amyloid-β levels.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) therapeutics require reducing brain amyloid beta (Aβ).
• Neprilysin (NEP) is an endogenous enzyme that degrades Aβ.
• Efficient delivery of therapeutic enzymes to the brain is a significant challenge.

Purpose of the Study:

• To investigate the efficacy of delivering neprilysin to the brain using a Brain Shuttle (BS) transport system.
• To evaluate the pharmacokinetic/pharmacodynamic relationships of BS-NEP constructs in blood and cerebrospinal fluid (CSF).
• To assess the potential of BS-mediated enzyme delivery for reducing central Aβ levels.

Main Methods:

• Fusion of the extracellular catalytic domain of NEP to active or inactive BS modules.
• Administration of BS-NEP constructs in dose-response and multiple dosing studies.
• Measurement of BS-NEP pharmacokinetics in blood and CSF.
• Quantification of Aβ levels in CSF and brain parenchyma.

Main Results:

• Systemic administration of NEP alone effectively degraded Aβ in blood but not in CSF.
• The BS-NEP construct with an active BS module achieved significant CSF exposure.
• Active BS-NEP led to substantial Aβ reduction in both CSF and brain parenchyma.
• A BS module targeting the transferrin receptor facilitated enzyme transport across the blood-brain barrier.

Conclusions:

• A Brain Shuttle (BS) system targeting the transferrin receptor enables the transport of Aβ-degrading enzymes across the blood-brain barrier.
• This strategy efficiently reduces Aβ levels in both CSF and brain parenchyma.
• BS-mediated delivery of neprilysin represents a promising therapeutic approach for Alzheimer's disease.