Macrophages play a critical role in regeneration following peripheral nerve injury. Hematogenous macrophages are recruited to the distal nerve segment and shape the injured nerve microenvironment to be more conducive to regeneration through the clearance of cellular debris and the production of neurotrophic factors. Enhanced macrophage recruitment and debris clearance has been observed in BACE1 KO mice. This phenotype could be the result of BACE1 activity in macrophages, other nerve resident cells (neurons, Schwann cells), or it could also be the result of the hypomyelination phenotype that is also observed in BACE1 KO mice. To date it is uncertain what potential mechanisms may be driving this enhanced recruitment and debris clearance phenotype. Further, it is unknown which cell types in the peripheral microenvironment contribute most towards this phenotype when BACE1 is deleted. BACE1 is a promiscuous enzyme and has many substrates, thus may play a role in a variety pathways that could result in this enhanced macrophage recruitment and debris clearance phenotype. This thesis discusses several known BACE1 substrates and how they could impact macrophages in the context of peripheral nerve regeneration. Previous work done in our lab suggests that elimination of expression of BACE1 in cells derived from bone marrow may recapitulate the enhanced macrophage recruitment and activity phenotype. This thesis utilizes a mouse model with macrophage specific deletion of BACE1 to investigate whether BACE1 expression by macrophages mediates the immumodulatory phenotype observed in global BACE1 KO mice. This thesis demonstrates that there is not enhanced recruitment of macrophages to the injured peripheral nerve following injury. This suggests that the elimination of BACE1 expression by macrophages is not essential for the increased recruitment phenotype observed in global BACE1 KO mice
