The Low-Density Lipoprotein Receptor-Related Protein Is a Pro-Survival Receptor in Schwann Cells: Possible Implications in Peripheral Nerve Injury

Campana, W. Marie; Li, X.; Dragojlovic, Nikola; Janes, Julie R.; Gaultier, Alban; Gonias, Steven L.

doi:10.1523/jneurosci.2709-06.2006

Cited by 87 publications

(204 citation statements)

References 64 publications

(80 reference statements)

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“…The increase in Schwann cell LRP1 α-chain observed after CCI in the mouse was consistent with our earlier finding that Schwann cell LRP1 β-chain is increased following crush injury in rats (20). To confirm this correlation, we reexamined naive and crushed rat nerve by immunohistochemistry, using α-chain-specific antibody.…”

Section: Resultssupporting

confidence: 89%

“…In uninjured rat sciatic nerve, LRP1 β-chain immunoreactivity localizes mainly to axoplasm (20). After nerve crush injury, which causes fulminant axonal degeneration, LRP1 β-chain immunoreactivity is substantially increased in Schwann cells, accompanied by an increase in LRP1 mRNA; however, the total level of LRP1 β-chain in the nerve, as determined by immunoblot analysis, is decreased by about 50%, probably reflecting loss of LRP1 protein from axons.…”

Section: Resultsmentioning

confidence: 96%

“…We used polyclonal antibody 2629, which recognizes the 515-kDa LRP1 α-chain, as opposed to the β-chain (20,37). In the uninjured mouse nerve, LRP1 α-chain immunoreactivity was localized primarily to axoplasm and, to a lesser extent, to other resident endoneural cells including Schwann cells ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblot analysis using LRP1 α-chain-specific antibody confirmed that the α-chain is increased in crushed nerve. Because the LRP1 α-chain is increased in crushed nerve ( Figure 1) and the β-chain is decreased (20), we hypothesized that the α-chain may be shed and remain stable in the extracellular microenvironment of the injured peripheral nerve.…”

Section: Resultsmentioning

confidence: 99%

“…In the peripheral nervous system (PNS), LRP1 promotes Schwann cell survival by regulating the activity of PI3K (20).…”

Section: Introductionmentioning

confidence: 99%

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A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Gaultier

Arandjelovic

et al. 2008

J. Clin. Invest.

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Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor-related protein-1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-α inhibited TNF-α-induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…In the peripheral nervous system (PNS), LRP1 promotes Schwann cell survival by regulating the activity of PI3K (20).…”

Section: Introductionmentioning

confidence: 99%

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A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Gaultier

Arandjelovic

et al. 2008

J. Clin. Invest.

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Metallothionein‐I+II in neuroprotection

et al. 2009

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Metallothionein (MT)-I+II synthesis is induced in the central nervous system (CNS) in response to practically any pathogen or disorder, where it is increased mainly in reactive glia. MT-I+II are involved in host defence reactions and neuroprotection during neuropathological conditions, in which MT-I+II decrease inflammation and secondary tissue damage (oxidative stress, neurodegeneration, and apoptosis) and promote post-injury repair and regeneration (angiogenesis, neurogenesis, neuronal sprouting and tissue remodelling). Intracellularly the molecular MT-I+II actions involve metal ion control and scavenging of reactive oxygen species (ROS) leading to cellular redox control. By regulating metal ions, MT-I+II can control metal-containing transcription factors, zinc-finger proteins and p53. However, the neuroprotective functions of MT-I+II also involve an extracellular component. MT-I+II protects the neurons by signal transduction through the low-density lipoprotein family of receptors on the cell surface involving lipoprotein receptor-1 (LRP1) and megalin (LRP2). In this review we discuss the newest data on cerebral MT-I+II functions following brain injury and experimental autoimmune encephalomyelitis.

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Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

Safina

Schlitt

Romeo

et al. 2016

Glia

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The LDL family of receptors and its member LRP1 have classically been associated with a modulation of lipoprotein metabolism. Current studies, however, indicate diverse functions for this receptor in various aspects of cellular activities, including cell proliferation, migration, differentiation and survival. LRP1 is essential for normal neuronal function in the adult CNS, whereas the role of LRP1 in development remained unclear. Previously we have observed an upregulation of LewisX (LeX) glycosylated LRP1 in the stem cells of the developing cortex and demonstrated its importance for oligodendrocyte differentiation. In the current study we show that LeX-glycosylated LRP1 is also expressed in the stem cell compartment of the developing spinal cord and has broader functions in the developing CNS. We have investigated the basic properties of LRP1 conditional knockout on the neural stem/progenitor cells (NSPCs) from the cortex and the spinal cord, created by means of Cre-loxp mediated recombination in vitro. The functional status of LRP1-deficient cells has been studied using proliferation, differentiation and apoptosis assays. LRP1 deficient NSPCs from both CNS regions demonstrated altered differentiation profiles. Their differentiation capacity towards oligodendrocyte progenitor cells (OPCs), mature oligodendrocytes and neurons was reduced. In contrast, astrocyte differentiation was promoted. Moreover, LRP1 deletion had a negative effect on NSPCs proliferation and survival. Our observations suggest that LRP1 facilitates NSPCs differentiation via interaction with ApoE. Upon ApoE4 stimulation wild type NSPCs generated more oligodendrocytes, but LRP1 knockout cells showed no response. The effect of ApoE seems to be independent of cholesterol uptake, but is rather mediated by downstream MAPK and Akt activation.

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The Low-Density Lipoprotein Receptor-Related Protein Is a Pro-Survival Receptor in Schwann Cells: Possible Implications in Peripheral Nerve Injury

Cited by 87 publications

References 64 publications

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

Metallothionein‐I+II in neuroprotection

Low‐density lipoprotein receptor‐related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation

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