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A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis


Year of Publication:
Contact PI Name:
Brian Spenser
Contact PI Affiliation:
NeuroTransit, Inc., San Diego, California, USA
Inder Verma, Paula Desplats, Dinorah Morvinski, Ed Rockenstein, Anthony Adame, Eliezer Masliah
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Study Goal and Principal Findings:

The delivery of proteases for the targeted degradation of Aβ is currently an untested therapeutic approach for AD. One such protease, neprilysin (NEP), a zinc metalloendopeptidase, has been identified as a critical Aβ-degrading enzyme in the CNS. Neprilysin has been shown to degrade Aβ monomers  and in some reports Aβ oligomers in vitro. Delivering neprilysin to the CNS has been difficult to achieve; peripheral delivery of neprilysin with viral vector-mediated gene delivery, ex vivo cellular manipulation, or intravenous recombinant protein delivery failed to deliver neprilysin enzyme to the CNS.  To address this problem the authors recently developed a neprilysin containing a brain-transport peptide that was able to reduce CNS Aβ and improve learning and memory in an APP Tg mouse model of AD. In this study , the authors characterize ASN12, a brain-targeted recombinant neprilysin protein, for pharmacology as well as efficacy in two Tg mouse models of AD. The authors found that the brain-targeted protein was transported across the blood-brain barrier and accumulated in the brain with a t1⁄2 of 24 h. Treatment of Tg2576 and APP TgLine 41  mice by repeated injections resulted in reduced intraneuronal Abeta , and attenuated Abeta induced neuropathology. In addition, mice treated with the brain-targeted neprilysin showed increased levels neurogenesis and improved performance in learning and memory tasks. These results suggest that ASN12 may be an effective treatment for AD and warrant further investigation in clinical trials. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Peptide
Therapeutic Agent:
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
B6;SJL Mixed Background
Model Type:
Strain/Genetic Background:
C57BL/6 × DBA/2 F1
Animal Model Notes:
Strain/Background info for the hAPP751 (line 41) mice is taken from the following: Rockenstein E., Mallory M., Mante M., Sisk A., Masliah E. (2001) Early formation of mature amyloid-β protein deposits in a mutant APP transgenic model depends on levels of Aβ(1–42). J. Neurosci. Res. 66, 573–582.

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
Intracellular beta Amyloid Peptide
Pyroglutamate Modified beta Amyloid Peptides
Microtubule-Associated Protein 2 (MAP2)
Cell Biology
Cell Uptake
Recombinant Protein Concentration-Blood
Area Under the Curve (AUC)
t1/2 (Elimination Half-Life)
Drug Concentration-Brain
ASN12 Concentration-Blood
Clearance (L/h/kg)
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Body Weight