N-methyl-d-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein

Abstract

The effects of a synthetic apoE1 peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor-binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, has been investigated. The activity of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was found to depend on the low density lipoprotein receptor-related protein (LRP). Competition experiments with receptor associated protein (RAP) and activated α 2 macroglobulin (α 2 M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and α 2 M*. A co-receptor of LRP, cell-surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE [133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] was 3-fold greater for NMDAR-transfected wild-type Chinese Hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR-inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

An Apolipoprotein E-Mimetic Stimulates Axonal Regeneration and Remyelination after Peripheral Nerve Injury

“…Another protective mechanism is related to glutamate excitotoxicity. Both apoE protein, as well as its mimetic peptide COG133, can prevent primary neurons from excitotoxicity-induced calcium influx and subsequent cell death (Aono et al, 2002(Aono et al, , 2003 through binding to the low-density lipoprotein receptor-associated protein (Sheng et al, 2008). A similar protective effect of COG112 was recently validated by our laboratory (F.-Q.…”

“…Similar to holo-apoE3 protein, COG133 inhibits lipopolysaccharide (LPS)-stimulated microglia activation, reduces TNF-␣ and NO production in vitro (Laskowitz et al, 2001), and suppresses brain and systemic inflammatory responses in LPS-injected mice . Likewise, apoE-mimetic peptides retain the ability to bind LRP1 and other LDL receptors (Croy et al, 2004) and simulate the neuroprotective effect of apoE protein against N-methyl-D-aspartate excitotoxicity (Sheng et al, 2008). To enhance transmembrane permeability, COG133 has been molecularly modified by fusion with a protein transduction domain (PTD) derived from Drosophila antennapedia protein (Antp) to create COG112.…”

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

“…In neurons, LRP1 signaling requires the NMDA-R as an essential co-receptor (Bacskai et al, 2000;Qiu et al, 2002;Samson et al, 2008;Martin et al, 2008;Sheng et al, 2008;Mantuano et al, 2013). Other LRP1 co-receptors in neurons include Trk receptors and p75 NTR (Shi et al, 2009;Yoon et al, 2013;Stiles et al, 2013).…”

“…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).…”

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

“…Protective effects of apoE have been observed in the context of coagulation, macrophage function, oxidative processes, central nervous system physiology, infl ammation, and cell signaling ( 98,99 ). Data suggest that anti-infl ammatory reduce infl ammatory injury in murine models of multiple sclerosis and traumatic brain injury, respectively, and are thought to mediate their effects via binding to LRP (128)(129)(130).…”