Abstract
Following peripheral nerve injury, multiple cell types, including axons, Schwann cells, and macrophages, coordinate to promote nerve regeneration. However, this capacity for repair is limited, particularly in older populations, and current treatments are insufficient. A critical component of the regeneration response is the network of cell-to-cell signaling in the injured nerve microenvironment. Sheddases are expressed in the peripheral nerve and play a role in the regulation if this cell-to-cell signaling through cleavage of transmembrane proteins, enabling the regulation of multiple pathways through cis- and trans-cellular regulatory mechanisms. Enhanced axonal regeneration has been observed in mice with deletion of the sheddase beta-secretase (BACE1), a transmembrane aspartyl protease that has been studied in the context of Alzheimer’s disease. BACE1 knockout (KO) mice display enhanced macrophage recruitment and activity following nerve injury, although it is unclear whether this plays a role in driving the enhanced axonal regeneration. Further, it is unknown by what mechanism(s) BACE1 increases macrophage recruitment and activity. BACE1 has many substrates, several of which are known to have immunomodulatory activity. This review will discuss current knowledge of the role of BACE1 and other sheddases in peripheral nerve regeneration and outline known immunomodulatory BACE1 substrates and what potential roles they could play in peripheral nerve regeneration. Currently, the literature suggests that BACE1 and substrates that are expressed by neurons and Schwann cells are likely to be more important for this process than those expressed by macrophages. More broadly, BACE1 may play a role as an effector of immunomodulation beyond the peripheral nerve.
Highlights
The peripheral nervous system (PNS) has a limited capacity for regeneration in response to injury that is insufficient to restore full function and mitigate morbidity and disability in humans
Regeneration following peripheral nerve injury is slow, but given the critical role macrophages play in regeneration, immunomodulation of these cells may present an opportunity to improve recovery and reduce morbidity associated with nerve injury
The substrate promiscuity of Beta-site APP cleaving enzyme 1 (BACE1) could promote robust immunomodulation by acting on many pathways to alter the interactions between neurons, Schwann cells, and macrophages in the peripheral nerve microenvironment
Summary
The peripheral nervous system (PNS) has a limited capacity for regeneration in response to injury that is insufficient to restore full function and mitigate morbidity and disability in humans. Another cohort of macrophages will persist in the distal nerve segment for at least 6 weeks following injury and provide pro-regenerative signaling molecules to the regenerating axons and Schwann cells [60, 61]. Pharmacological inhibition of BACE1 in mice following nerve injury results in increased numbers of regenerating axons, reinnervated NMJs, and improved functional recovery [71].
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