Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Yoon, Choya; Niekerk, Erna A. van; Henry, Kenneth W.; Ishikawa, Tetsuhiro; Orita, Sumihisa; Tuszynski, Mark H.; Campana, W. Marie

doi:10.1074/jbc.m113.478552

Cited by 43 publications

(58 citation statements)

References 56 publications

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“…Previously, a correlation between decreased Akt phosphorylation and caspase-3 activation was demonstrated in LRP1 knocked-down neurons (Fuentealba et al, 2009). Another recent study demonstrated that treatment of neurons with LRP1 agonists induces TrkC, Akt, and ERK activation and increases neurite outgrowth (Yoon et al, 2013). Our study found that Akt activation decreased in neurons under ischemic conditions and it was further decreased in the presence of the LRP1 antagonist RAP.…”

Section: Discussionmentioning

confidence: 58%

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Lok

Manzanero

2016

Brain Research

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Section: Discussionmentioning

confidence: 58%

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Lok

Manzanero

2016

Brain Research

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“…Recently, it was reported that complement protein C1q protected both immature and mature primary cortical neurons against fibrillar and oligomeric Aβ-mediated neurotoxicity possibly through a neuroprotective response that involves the upregulation of LRP1B [118]. Further evidence of the neuroprotective role of LRP-1 was recently found: LRP-1-dependent cell signaling via TrkC activation promoted axonal growth in the CNS after injury, suggesting a clear contribution of LRP-1 to neuronal plasticity [119]. Sagare and colleagues [120] further explored LRP-1 as a target and showed that 3-month treatment of an AD mouse model with LRPIV-D3674G, a mutant receptor with higher affinity to Aβ 40 and Aβ 42 in vitro and lower affinity to other LRP-1 ligands, given subcutaneously at 40 μg/kg/day, reduced Aβ 1-40 and Αβ 1-42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80 % and enhanced CBF and hippocampal function at 9 months of age.…”

Section: Changes In Amyloid-β Transportersmentioning

confidence: 96%

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

2015

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".

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“…This interaction might be potentiated by ligand binding to LRP1 . Trk receptors also are required for cell signaling downstream of LRP1 and the NMDA-R in neurons and neuron-like cells (Shi et al, 2009;Yoon et al, 2013). Because we do not have evidence for the function of Trk receptors in LRP1 signaling in Schwann cells (Shi et al, 2009), the activity of other receptor tyrosine kinases merits consideration.…”

Section: Discussionmentioning

confidence: 99%

“…Other LRP1 co-receptors in neurons include Trk receptors and p75 NTR (Shi et al, 2009;Yoon et al, 2013;Stiles et al, 2013). Very little is known about the molecular nature of the LRP1 signaling system in other cell types.…”

Section: Nmda-r Is Necessary For Lrp1 Signaling In Schwann Cellsmentioning

confidence: 99%

“…Based on its interaction with LRP1, the NMDA-R functions as an essential signaling co-receptor for LRP1 ligands, including α 2 -macroglobulin (α 2 M), tissue-type plasminogen activator (tPA) and apolipoprotein E (Bacskai et al, 2000;Qiu et al, 2002;Samson et al, 2008;Martin et al, 2008;Sheng et al, 2008;Mantuano et al, 2013). LRP1 ligands have been implicated in neuronal survival (Hayashi et al, 2007;Fuentealba et al, 2009) and in neurite outgrowth (Mantuano et al, 2008a,b;Shi et al, 2009;Yoon et al, 2013). Unlike other LRP1 ligands, tPA interacts directly with the NMDA-R, independently of LRP1, triggering cell signaling, albeit with delayed kinetics (Nicole et al, 2001;Macrez et al, 2010;Ng et al, 2009;Mantuano et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

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NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury.

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Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Cited by 43 publications

References 56 publications

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Neuronal low-density lipoprotein receptor-related protein 1 (LRP1) enhances the anti-apoptotic effect of intravenous immunoglobulin (IVIg) in ischemic stroke

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

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