Asparagine endopeptidase (delta secretase), an enzyme implicated in Alzheimer's disease pathology, is an inhibitor of axon regeneration in peripheral nerves

• Type of Material: Article
• Authors: Arthur English, Emory University; Xia Liu, Emory University; Olivia C Mistretta, Emory University; Patricia Ward, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: SOC NEUROSCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 English et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/ENEURO.0155-20.2020
• Title of Journal or Parent Work: ENEURO
• Volume: 8
• Issue: 1
• Start Page: 1
• End Page: 13
• Grant/Funding Information: This work was supported by National Institutes of Health Grant NS105982 from the United States Public Health Service.
• Keywords: Neurosciences; GROWTH; INJURY; SCHWANN-CELLS; TISSUE; asparagine endopeptidase; EXPRESSION; APP; Science & Technology; mouse; MICROTUBULES; Tau; ORGANIZATION; ELECTRICAL-STIMULATION PROMOTES; Neurosciences & Neurology; FUNCTIONAL RECOVERY; regeneration; nerve; TAU; Life Sciences & Biomedicine
• Research Categories: Biology, Cell; Health Sciences, Pathology

Abstract

Asparagine endopeptidase (AEP) is a lysosomal protease implicated in the pathology of Alzheimer’s disease (AD). It is known to cleave the axonal microtubule associated protein, Tau, and amyloid precursor protein (APP), both of which might impede axon regeneration following peripheral nerve injury (PNI). Active AEP, AEPcleaved fragments of Tau (Tau N368), and APP (APP N585) were found in injured peripheral nerves. In AEP null mice, elongation of regenerating axons after sciatic nerve transection and repair was increased relative to wild-type (WT) controls. Compound muscle action potentials (M responses) were restored in reinnervated muscles twice as fast after injury in AEP knock-out (KO) mice as WT controls. Neurite elongation in cultures of adult dorsal root ganglion (DRG) neurons derived from AEP KO mice was increased significantly relative to cultures from WT controls. In AEP KO mice exposed to 1 h of 20-Hz electrical stimulation (ES) at the time of nerve injury, no further enhancement of axon regeneration was observed. These findings support inhibition of AEP as a therapeutic target to enhance axon regeneration after PNI.