Abstract
Low-density lipoprotein receptors (LRPs) are present extensively on cells outside of the nervous system and classically exert roles in lipoprotein metabolism. It has been reported recently that LRP1 activation could phosphorylate the neurotrophin receptor TrkA in PC12 cells and increase neurite outgrowth from developing cerebellar granule cells. These intriguing findings led us to explore the hypothesis that LRP1 activation would activate canonical neurotrophic factor signaling in adult neurons and promote axonal regeneration after spinal cord injury. We now find that treatment of adult rat dorsal root ganglion neurons in vitro with LRP1 agonists (the receptor binding domain of α-2-macroglobulin or the hemopexin domain of matrix metalloproteinase 9) induces TrkC, Akt, and ERK activation; significantly increases neurite outgrowth (p < 0.01); and overcomes myelin inhibition (p < 0.05). These effects require Src family kinase activation, a classic LRP1-mediated Trk transactivator. Moreover, intrathecal infusions of LRP1 agonists significantly enhance sensory axonal sprouting and regeneration after spinal cord injury in rats compared with control-infused animals (p < 0.05). A significant role is established for lipoprotein receptors in sprouting and regeneration after CNS injury, identifying a novel class of therapeutic targets to explore for traumatic neurological disorders.
Highlights
LDL receptor-related protein 1 (LRP1) Is Expressed in Adult dorsal root ganglion (DRG) Neurons, and LRP1 Activation Increases Neurite Outgrowth—Double labeling for LRP1 and neurofilament 200 (NF200), a marker for large-diameter neurons [30], demonstrated that LRP1 is expressed by intact adult, large-diameter DRG neurons and some smaller DRG neurons (Fig. 1A)
Intrathecal infusions of LRP1 agonists result in significant increases in axonal sprouting and regeneration after spinal cord injury
These findings indicate that targeting of lipoprotein receptors can activate cell signaling relevant to axonal growth in vitro and in vivo
Summary
LRP1 agonists were reported to induce transactivation of TrkA in a Src family kinase (SFK)3dependent manner, promoting neurite outgrowth from PC12 cells [23] The latter findings identify a candidate mechanism for potential actions of LRP1 on axonal function and suggest the hypothesis that LRP1 activation could promote axonal sprouting and regeneration in the adult CNS. We report potent effects of LRP1-binding ligands on axonal growth in vitro and after spinal cord injury in vivo, identifying a novel LRP1-dependent cell signaling mechanism involved in CNS plasticity and regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
