Multiple pathways of apolipoprotein E signaling in primary neurons

Hoe, Hyang‐Sook; Harris, Dorothy; Rebeck, G. William

doi:10.1111/j.1471-4159.2004.03007.x

Cited by 107 publications

(117 citation statements)

References 48 publications

(123 reference statements)

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“…Activation of the AKT and ERK pathways was through the LRP1 receptor (83). A tandem repeat ApoE mimetic peptide also induced phosphorylation of Dab-1 independent of effects on ERK and AKT signaling (84). ApoE signaling may also inhibit normal Reelin signaling (19).…”

Section: Discussionmentioning

confidence: 99%

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Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Divekar

Burrell

Lee

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…ApoE induces phosphorylation of the AKT and ERK pathways and inhibition of the JNK pathway (83)(84)(85). Activation of the AKT and ERK pathways was through the LRP1 receptor (83).…”

Section: Discussionmentioning

confidence: 99%

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Divekar

Burrell

Lee

et al. 2014

Journal of Biological Chemistry

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“…Studies from several groups have demonstrated that apoE receptors affect kinase signaling cascades by affecting calcium influx (5,7,24,26). Another study showed a direct effect of apoE receptors on calcium influx via NMDA receptors (4).…”

Section: Discussionmentioning

confidence: 99%

“…Data were analyzed using analysis of variance with Graphpad Prism 4 software, using Tukey's Multiple Comparison test for post-hoc analyses with significance determined as p Ͻ 0.05. cellular kinase activation, including activating extracellular signal-regulated kinase 1/2 (ERK 1/2) (7). ERK 1/2 activation required active NMDA receptors and calcium influx, suggesting that some apoE receptors interact with NMDA receptors (7). To test whether ApoEr2 directly interacted with the NMDA receptor, we transfected COS7 cells with ApoEr2 and NR1, immunoprecipitated NR1, and probed the precipitates with anti-HA.…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E Receptor 2 Interactions with the N-Methyl-D-aspartate Receptor

Hoe

Pocivavsek

Chakraborty

et al. 2006

Journal of Biological Chemistry

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In our previous studies we showed that apoE treatment of neurons activated ERK 1/2 signaling, and activation was blocked by treatment with inhibitors of the low density lipoprotein receptor family, the N-methyl-D-aspartate (NMDA) receptor antagonist MK 801, and calcium channel blockers. We hypothesized an interaction between the low density lipoprotein receptor family members and the NMDA receptor. In the present study, we confirmed through co-immunoprecipitation experiments an interaction between the apoE receptor, ApoEr2, and NMDAR1 through their extracellular domains. We also found that the PDZ1 domain of PSD95, a postsynaptic scaffolding protein, interacted with the C terminus of ApoEr2 via an alternatively spliced, intracellular exon. This interaction between ApoEr2 and PSD95 in neurons was modulated by NMDA receptor activation and an ApoEr2 ligand. We also found that the PDZ2 domain of PSD95 interacted with the NR2A and NR2B subunits of NMDA receptors. Full-length PSD95 increased cell surface levels of ApoEr2 and its cleavage, resulting in increases in secreted ApoEr2 and C-terminal fragments of ApoEr2. These studies suggest that ApoEr2 can form a multiprotein complex with NMDA receptor subunits and PSD95. Apolipoprotein E (apoE)2 allows lipoproteins to introduce a variety of lipophilic molecules to cells (1). Cholesterol and lipids are essential in remodeling neuronal membranes and developing new growth terminals. These processes mediate synaptic plasticity and responses to neurodegeneration. ApoE-containing lipoproteins are endocytosed into cells via apoE receptors, including the low density lipoprotein receptor, low density lipoprotein receptor-related protein (LRP1), very low density lipoprotein receptor, apoE receptor type 2 (ApoEr2), and the LR11 receptor (2). Ligand activation of these receptors has also been implicated in a variety of neuronal signaling processes. These receptors play roles in neuronal migration during development (3), calcium influx through the NMDA channel (4, 5), and neurite outgrowth (6). Our previous work showed that apoE and an apoE-derived peptide also activated the extracellular signal-regulated kinase 1/2 (ERK 1/2) (7). The activation of ERK 1/2 by apoE was blocked by an inhibitor to the low density lipoprotein receptor family, the NMDA receptor antagonist MK 801, and calcium channel blockers. We also found that apoE promoted extracellular and intramembranous cleavages of these receptors, affecting metabolism of their C-terminal fragments (8).Several in vivo and in vitro studies have supported roles for apoE and apoE receptors in signaling processes involving NMDA channels. ApoE targeted replacement mice revealed that long term potentiation (LTP) was significantly greater in animals expressing mouse apoE or human apoE3 than in apoE knock-out (9), apoE2, or apoE4 mice (10). Mice deficient in the very low density lipoprotein receptor and ApoEr2 also have moderate defects in LTP (11). Biochemical and immunohistochemical studies showed that the LRP1 interacts with NMDA recepto...

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“…The lipoprotein receptors ApoER2 and VLDLR can activate pro-survival signaling through the inactivation of the JNK-pathway and by increasing PI3K and ERK1/2 activity [29]. Proprotein convertase subtilisin/kexin type 9 has the ability to bind and degrade ApoER2 and VLDLR [7].…”

Section: Cells Protected By Pcsk9 Rnai Exhibit Altered Levels Of Lipomentioning

confidence: 99%

PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

Kysenius

Muggalla

Mätlik

et al. 2012

Cell. Mol. Life Sci.

112

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The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAimediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporineinduced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways.

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Multiple pathways of apolipoprotein E signaling in primary neurons

Cited by 107 publications

References 48 publications

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

Apolipoprotein E Receptor 2 Interactions with the N-Methyl-D-aspartate Receptor

PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

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