The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve

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.

Single-cell and spatial multiomic inference of gene regulatory networks using SCRIPro

“…For example, we observed a high enrichment of NOTCH1 activity in the LV region (D9), which is known to harbor neural stem cells. Interestingly, its upstream regulator Dlk1/2[62] and Jagged1[63] were found to have closer associations with the NOTCH1 regulon in the LV region compared to the CC region (D6) and CT region (D0) (Fig. 6E).…”

Enhanced sciatic nerve regeneration by relieving iron-overloading and organelle stress with the nanofibrous P(MMD-co-LA)/DFO conduits

“…Soon after peripheral nerve injury, WD of the distal nerve stump begins with the degeneration and disintegration of axons and the dedifferentiation of Schwann cells [ 50 ]. Schwann cells decompose myelin and recruit macrophages, which mediate the initial inflammatory response [ 50 , 51 ]. Obviously, the inflammatory response caused by PNI in the PDPLA group is more intense, but it can be effectively relieved after DFO loading.…”

Peripheral Nerve Injury Treatments and Advances: One Health Perspective

“…PNI is a condition that affects the quality of life of many people and leads to motor and sensory deficits (19). The positive point is that the PNS has some regeneration capacity, and the minor lesions can heal with full, or almost full, functional recovery in some cases (16).…”

“…Macrophages, neutrophils, endothelial cells and SCs are very important in the different stages of the peripheral nerve repair mechanism. SCs proliferate, phagocyte debris in the lesion site and mobilize macrophages to promote the optimal regenerative surroundings [18,19]. Also, SCs form the myelin sheath along peripheral nerves and are responsible for the formation of the bands of Bunger [20].…”