Pharmacological BACE Inhibition Improves Axonal Regeneration in Nerve Injury and Disease Models.

ABSTRACT

While the peripheral nervous system is able to repair itself following injury and disease, recovery is often slow and incomplete, with no available treatments to enhance the effectiveness of regeneration. Using knock-out and transgenic overexpressor mice, we previously reported that BACE1, an aspartyl protease, as reported by Hemming et al. (PLoS One 412, 2009), negatively regulates peripheral nerve regeneration. Here, we investigated whether pharmacological inhibition of BACE may enhance peripheral nerve repair following traumatic nerve injury or neurodegenerative disease. BACE inhibitor-treated mice had increased numbers of regenerating axons and enhanced functional recovery after a sciatic nerve crush while inhibition increased axonal sprouting following a partial nerve injury. In the SOD1G93A ALS mouse model, BACE inhibition increased axonal regeneration with improved muscle re-innervation. CHL1, a BACE1 substrate, was elevated in treated mice and may mediate enhanced regeneration. Our data demonstrates that pharmacological BACE inhibition accelerates peripheral axon regeneration after varied nerve injuries and could be used as a potential therapy.