Department of Neurology, Neuromuscular Division, Johns Hopkins University School of Medicine, The John G. Rangos Sr. Building, Room 239, 855 N. Wolfe Street, Baltimore, MD, 21205, USA.
Merck & Co, Boston, MA, USA.
Neurotherapeutics. 2020 Jul;17(3):973-988. doi: 10.1007/s13311-020-00852-3.
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 4:12, 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 SOD1 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.
虽然周围神经系统在受伤和疾病后能够自我修复，但恢复通常缓慢且不完整，没有可用的治疗方法来增强再生的效果。我们之前曾使用敲除和转基因过表达小鼠报告，天冬氨酸蛋白酶 BACE1（Hemming 等人，PLoS One 4：12，2009）可负向调节周围神经再生。在这里，我们研究了抑制 BACE 是否可以增强外伤性神经损伤或神经退行性疾病后的周围神经修复。用 BACE 抑制剂治疗的小鼠在坐骨神经挤压后具有更多数量的再生轴突和增强的功能恢复，而抑制在部分神经损伤后增加轴突发芽。在 SOD1 ALS 小鼠模型中，BACE 抑制增加了轴突再生，改善了肌肉再支配。BACE1 的底物 CHL1 在治疗小鼠中升高，可能介导增强的再生。我们的数据表明，药理 BACE 抑制可加速各种神经损伤后的周围轴突再生，可作为一种潜在的治疗方法。
