Schwann cell LRP1 is essential for conserving myelin and mitochondrial integrity in aged peripheral nerves

Introduction: Mitochondria are dynamic organelles, the abundance, size, and function of which are regulated by mitochondrial fission, fusion, and mitophagy. In the PNS, structurally abnormal mito¬chondria in Schwann cells (SCs) have been associated with peripheral neuropathy. The endocytic and cell- signaling transmembrane receptor, low-density lipoprotein receptor-related protein-1 (LRP1), is expressed in uninjured nerve and is substantially up-regulated in SCs after PNS injury. SC LRP1 contributes to the SC Repair Program. Herein, we assessed the activity of SC LRP1 in the aging PNS. Methods: Adult female scLRP1flox/flox-Mpz-Cre-positive (scLRP1-/-) and scLRP1flox/flox-Mpz-Cre-negative (scLRP1+/+) mice (12-24 month-old) were studied (n=4mice/genotype). Aged sciatic nerves were placed in Karnovsky's fixative and embedded in epoxy resin. Ultrathin transverse nerve sections (60 nm) were cut and post-stained. Sections were viewed using a JEOL1200EX II transmission electron microscope and photographed using a Gatan digital camera. Electron micrographs (~2000) were used for all quantifications. For analysis of Remak bundles and myelinated fibers, at least 6 random fields per mouse were evaluated. Results: scLRP1-/- mice demonstrated progressive failure of myelin maintenance and diverse abnormalities in unmyelinated SCs (cytoplasmic protrusions, collagen pockets). However, the overall number of myelinated and unmyelinated fibers, and Remak bundles was unchanged. The 1 of 4 4/27/2022, 8:19 PM PNS https://ww3.aievolution.com/pns2201/index.cfm?do=abs.viewAbs&sub... abundance of mito¬chondria was significantly increased in myeli¬nating (P<0.01) and non- myelinating (P<0.01) SCs. Importantly, the increase in abundance of mitochondria was not limited to SCs, but also identified in unmyelinated (P<0.01) and myelinated axons (P<0.05). An increased fraction of mitochondria in scLRP1-/- mouse nerves appeared swollen with loss of well- defined cristae; these changes may be observed in pre-apoptotic cells. scLRP1-/- nerves demonstrated an increase in number of vacuoles in Remak bundle axons (P<0.01). Conclusions: These ultrastructure studies demonstrate that SC LRP1 contributes to myelin maintenance and axonal integrity in aging nerves, at least in part via pathways that regulate mitochondrial abundance and function.