Increased BACE1 activity inhibits peripheral nerve regeneration after injury

Carolyn Tallon, Edward Rockenstein, Eliezer Masliah, Mohamed H Farah

Research output: Contribution to journalArticle

Abstract

Axons of the peripheral nervous system possess the capacity to regenerate following injury. Previously, we showed that genetically knocking out Beta-Site APP-Cleaving Enzyme 1 (BACE1) leads to increased nerve regeneration. Two cellular components, macrophages and neurons, contribute to enhanced nerve regeneration in BACE1 knockout mice. Here, we utilized a transgenic mouse model that overexpresses BACE1 in its neurons to investigate whether neuronal BACE1 has an inverse effect on regeneration following nerve injury. We performed a sciatic nerve crush in BACE1 transgenic mice and control wild-type littermates, and evaluated the extent of both morphological and physiological improvements over time. At the earliest time point of 3 days, we observed a significant decrease in the length of axonal sprouts growing out from the crush site in BACE1 transgenic mice. At later times (10 and 15 days post-crush), there were significant reductions in the number of myelinated axons in the sciatic nerve and the percentage of re-innervated neuromuscular junctions in the gastrocnemius muscle. Transgenic mice had a functional electrophysiological delay in the recovery up to 8 weeks post-crush compared to controls. These results indicate that BACE1 activity levels have an inverse effect on peripheral nerve repair after injury. The results obtained in this study provide evidence that neuronal BACE1 activity levels impact peripheral nerve regeneration. This data has clinical relevance by highlighting a novel drug target to enhance peripheral nerve repair, an area which currently does not have any approved therapeutics.

Original languageEnglish (US)
Pages (from-to)147-157
Number of pages11
JournalNeurobiology of Disease
Volume106
DOIs
StatePublished - Oct 1 2017

Keywords

  • BACE1
  • Peripheral nerve regeneration
  • Sciatic nerve crush

ASJC Scopus subject areas

  • Neurology

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