Pharmacological BACE Inhibition Improves Axonal Regeneration in Nerve Injury and Disease Models.
Pharmacological BACE Inhibition Improves Axonal Regeneration in Nerve Injury and Disease Models.
复制标题
药理学 BACE 抑制可改善神经损伤和疾病模型中的轴突再生。
DOI：
10.1007/s13311-020-00852-3
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Farah,MohamedH
中科院分区：
文献类型：
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作者：
Tallon,Carolyn;Marshall,KatherineL;Kennedy,MatthewE;Hyde,LynnA;Farah,MohamedH
虽然周围神经系统能够在损伤和疾病后自我修复，但恢复通常是缓慢和不完全的，没有可用的治疗方法来提高再生的有效性。使用敲除和转基因过表达小鼠，我们先前报道了BACE1（一种乙酰基蛋白酶），如Hemming等人（PLoS One 4：12，2009）所报道的，负调节外周神经再生。在这里，我们研究了药物抑制BACE是否可以增强创伤性神经损伤或神经退行性疾病后的周围神经修复。BACE受体处理的小鼠在坐骨神经挤压后再生轴突的数量增加，功能恢复增强，而抑制增加了部分神经损伤后的轴突发芽。在SOD1G93AALS小鼠模型中，BACE抑制增加了轴突再生，改善了肌肉神经再支配。CHL1，BACE1底物，在治疗的小鼠中升高，并可能介导增强再生。我们的数据表明，药理学BACE抑制加速周围轴突再生后，各种神经损伤，并可用作一种潜在的治疗。
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 SOD1G93AALS 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.