Asparagine Endopeptidase (δ Secretase), an Enzyme Implicated in Alzheimer's Disease Pathology, Is an Inhibitor of Axon Regeneration in Peripheral Nerves.

Arthur W English,Patricia J Ward,Olivia C Mistretta,Keqiang Ye,Xia Liu

doi:10.1523/eneuro.0155-20.2020

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, AEP-cleaved 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.

Highlights

Only ;10% of .200,000 new traumatic peripheral nerve injuries (PNIs) that occur in the United States each year ever recover function (Frostick et al, 1998; Scholz et al, 2009), there is currently no widely used non-surgical treatment available
amyloid precursor protein (APP) is cleaved by Asparagine endopeptidase (AEP) and because of its association with neurite elongation and axon guidance (Southam et al, 2019), its degradation by AEP might be expected to slow or disrupt axon regeneration after PNI
We wanted to investigate whether AEP activity after PNI could inhibit axon regeneration, as predicted from our hypothesis

Summary

Introduction

Only ;10% of .200,000 new traumatic peripheral nerve injuries (PNIs) that occur in the United States each year ever recover function (Frostick et al, 1998; Scholz et al, 2009), there is currently no widely used non-surgical treatment available. Enhancing axon regeneration has emerged as a goal for the development of new treatments following PNI (Höke and Brushart, 2010). Following injury to a peripheral nerve, regenerative sprouts in the proximal segment lead to formation of regenerating axons that pass into a regeneration pathway. Received April 24, 2020; accepted November 23, 2020; First published December 14, 2020. The authors declare no competing financial interests.

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