Soluble Low-Density Lipoprotein Receptor–Related Protein

Grimsley, Philip G.; Quinn, Kathryn; Owensby, D.

doi:10.1016/s1050-1738(98)00029-2

Cited by 15 publications

(11 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activities of purified sLRP-α demonstrated here do not discount the possibility that significant shedding of LRP1 in vivo also may regulate cell physiology by loss of function of the membraneanchored receptor (59,67). In the PNS, shedding may adversely affect Schwann cell survival because membrane-anchored LRP1 controls the activity of PI3K and caspase activation in response to stress (20).…”

Section: Figurementioning

confidence: 65%

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.

View full text Add to dashboard Cite

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.

show abstract

Section: Figurementioning

confidence: 65%

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.

View full text Add to dashboard Cite

show abstract

“…First, LRP1 undergoes ectodomain shedding, which is mediated by metalloproteases (MMPs), from a region close to the membrane, releasing a soluble form of LRP1 (sLRP1) that is capable of binding ligands (ligand-binding domains shown in pink)146,147. LRP1 shedding occurs under physiological conditions, as evidenced by abundant sLRP1 in human plasma146,148. Second, LRP1 associates with BACE1 in lipid rafts and is a substrate for BACE1149.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

2009

Nat Rev Neurosci

996

883

View full text Add to dashboard Cite

PREFACEThe vast majority of Alzheimer's disease (AD) cases are late-onset and their development is likely influenced by both genetic and environmental risk factors. A strong genetic risk factor for lateonset AD is the presence of the ε4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. Mounting evidence demonstrates that apoE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-β peptide and by directly regulating brain lipid metabolism and synaptic functions through apoE receptors. Emerging knowledge on the contribution of apoE to the pathophysiology of AD presents new opportunities for AD therapy. INTRODUCTIONAlzheimer's disease (AD) is the most common cause of dementia in the elderly. Extracellular amyloid plaques and intracellular neurofibrillary tangles are defining lesions in AD 1,2 . Mounting genetic and biochemical data support the hypothesis that amyloid-β(Aβ) accumulation and aggregation in the brain is an early and central event in the pathogenesis of AD 2,3 . Aβ is derived from sequential proteolytic processing of the amyloid precursor protein (APP) by β-and γ-secretases. Mutations associated with early-onset familial AD (FAD) are dominantly inherited and are found in the APP gene itself or in the genes of presenilin 1 (PSEN1) and PSEN2, whose products, together with nicastrin, APH-1 and PEN-2, are essential components of a multi-protein complex that is responsible for γ-secretase activity 4 . A common feature of most FAD mutations is that they increase the generation of Aβ peptides, or increase the proportion of the longer Aβ42 form, which has a higher tendency to aggregate and is more toxic than the shorter Aβ40 3 . Because γ-secretase cleavage of an increasingly recognized panel of substrates is important for synaptic function and neuronal survival, a loss-of-function hypothesis for PSEN mutations in AD pathogenesis has also been proposed 5 .FAD genetics and mouse models have shed light on early-onset AD pathogenesis, but the vast majority of AD cases occur late in life. The ε4 allele of the apolipoprotein E (APOE) gene is a major risk for late-onset AD (LOAD). This risk allele, discovered in 1993 by Strittmatter, Roses and colleagues 6,7 , has been validated in numerous genetic association studies (see AlzGene website at http://www.alzforum.org/res/com/gen/alzgene/default.asp). Although a gene on chromosome 19 had previously been implicated in LOAD risk, the Correspondence to: Guojun Bu, Department of Pediatrics, Washington University School of Medicine, CB 8208, 660 South Euclid Ave, St. Louis, MO 63110, USA, Phone: 314-286-2860, Fax: 314-286-2894 Competing interests statement The author declares no competing financial interest. NIH Public Access Author ManuscriptNat Rev Neurosci. Author manuscript; available in PMC 2010 July 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript observation that apoE binds to Aβ in the cerebrospinal fluid (CSF) prompted the testing of APOE ...

show abstract

“…The soluble receptor is generated via proteolytic cleavage at an extracellular region close to the cell surface, a process called ectodomain shedding (Begg et al 2004; Etique et al 2013; Selvais et al 2010). When the soluble receptor is released from the cellular membrane, it retains the ability to bind ligands in the extracellular space (Grimsley et al 1998; Quinn et al 1997), but loses its functional capacity to internalize or transcytose ligands intracellularly (Rebeck et al 2006; Selvais et al 2010). It is believed the soluble receptor operates in a dominant negative fashion by attenuating the interaction between ligands and the membrane-associated receptor, thereby modulating endocytic activity and cell signaling (Etique et al 2013; Rebeck et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing

et al. 2014

View full text Add to dashboard Cite

Recent findings indicate an isoform-specific role for apolipoprotein E (apoE) in the elimination of beta-amyloid (Aβ) from the brain. ApoE is closely associated with various lipoprotein receptors, which contribute to Aβ brain removal via metabolic clearance or transit across the blood-brain barrier (BBB). These receptors are subject to ectodomain shedding at the cell surface, which alters endocytic transport and mitigates Aβ elimination. To further understand the manner in which apoE influences Aβ brain clearance, these studies investigated the effect of apoE on lipoprotein receptor shedding. Consistent with prior reports, we observed an increased shedding of the low density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1) following Aβ exposure in human brain endothelial cells. When Aβ was co-treated with each apoE isoform, there was a reduction in Aβ-induced shedding with apoE2 and apoE3, while lipoprotein receptor shedding in the presence of apoE4 remained elevated. Likewise, intracranial administration of Aβ to apoE targeted replacement mice (expressing the human apoE isoforms) resulted in an isoform-dependent effect on lipoprotein receptor shedding in the brain (apoE4>apoE3>apoE2). Moreover, these results show a strong inverse correlation with our prior work in apoE transgenic mice in which apoE4 animals showed reduced Aβ clearance across the BBB compared to apoE3 animals. Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing Aβ from the brain.

show abstract

Soluble Low-Density Lipoprotein Receptor–Related Protein

Cited by 15 publications

References 42 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

Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing

Contact Info

Product

Resources

About