Asparagine Endopeptidase (Delta Secretase), An Enzyme Implicated In Alzheimer'S Disease Pathology, Is An Inhibitor Of Axon Regeneration In Peripheral Nerves

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. 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 knockout mice as WT controls. Neurite elongation in cultures of adult dorsal root ganglion neurons derived from AEP knockout mice was increased significantly relative to cultures from wild type controls. In AEP knockout mice exposed to one hour of 20 Hz electrical stimulation 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 peripheral nerve injury.Significance StatementAxons in injured peripheral nerves can regenerate, but recovery from such injuries is poor. Asparagine endopeptidase (AEP) is an enzyme linked to the major pathological features of Alzheimer's disease. We show here that it is highly expressed in injured peripheral nerves and both reduces the microtubule stabilizing effect of Tau on axons and degrades amyloid precursor protein in a manner that hinders any axon pathfinding role. Removing AEP by gene knockout enhanced the elongation of regenerating axons in cut nerves and promoted an accelerated restoration of neuromuscular function. Inhibition of AEP is thus a target for development of novel strategies to treat peripheral nerve injuries.