The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease

Lane-Donovan, Courtney; Herz, Joachim

doi:10.1194/jlr.r075507

Cited by 75 publications

(64 citation statements)

References 89 publications

(90 reference statements)

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“…4,5,[8][9][10][11][12] Low-density lipoprotein (LDL) receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor-2 (APOER2), belongs to a superfamily of single-pass transmembrane receptors comprising LDL receptors (LDLR) and LDLR-related proteins (LRPs). 13,14 LRP8 displays high levels of sequence identity (50% in for the amino acid sequence) with the very-low-density lipoprotein receptor (VLDLR). 13 These two receptors have Reelin as a common ligand.…”

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confidence: 99%

“…13 These two receptors have Reelin as a common ligand. 15 LRP8 regulates neuronal differentiation and migration 13,14 and also functions in the brain, as a receptor for the cholesterol transport protein apolipoprotein E (ApoE), which has been reported to be a genetic risk factor of Alzheimer's disease. 16 LRP8 has also been reported to be a novel activator of the Wnt/β-catenin signaling pathway during osteoblast differentiation.…”

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confidence: 99%

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LRP8 is overexpressed in estrogen‐negative breast cancers and a potential target for these tumors

et al. 2018

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Triple‐negative breast cancer (TNBC) is the breast cancer subtype with the worst prognosis. New treatments improving the survival of TNBC patients are, therefore, urgently required. We performed a transcriptome microarray analysis to identify new treatment targets for TNBC. We found that low‐density lipoprotein receptor‐related protein 8 (LRP8) was more strongly expressed in estrogen receptor‐negative breast tumors, including TNBCs and those overexpressing HER2, than in luminal breast tumors and normal breast tissues. LRP8 depletion decreased cell proliferation more efficiently in estrogen receptor‐negative breast cancer cell lines: TNBC and HER2 overexpressing cell lines. We next focused on TNBC cells for which targeted therapies are not available. LRP8 depletion induced an arrest of the cell cycle progression in G1 phase and programmed cell death. We also found that LRP8 is required for anchorage‐independent growth in vitro, and that its depletion in vivo slowed tumor growth in a xenograft model. Our findings suggest that new approaches targeting LRP8 may constitute promising treatments for hormone‐negative breast cancers, those overexpressing HER2 and TNBCs.

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LRP8 is overexpressed in estrogen‐negative breast cancers and a potential target for these tumors

et al. 2018

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“…Reelin has been implicated in the onset or aggravation of many neuropsychiatric and neurodegenerative disorders 4,[6][7][8][9]16 . In almost all of the cases, the Reelin hypoactivity worsens them 1,16 .…”

Section: Discussionmentioning

confidence: 99%

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Okugawa

Ogino

Shigenobu

et al. 2020

Sci Rep

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Reelin is a secreted protein that plays versatile roles in neuronal development and function. The strength of Reelin signaling is regulated by proteolytic processing, but its importance in vivo is not yet fully understood. Here, we generated Reelin knock-in (PA-DV KI) mice in which the key cleavage site of Reelin was abolished by mutation. As expected, the cleavage of Reelin was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice. The amount of Dab1, whose degradation is induced by Reelin signaling, decreased in these tissues, indicating that the signaling strength of Reelin was augmented. The brains of PA-DV KI mice were largely structurally normal, but unexpectedly, the hippocampal layer was disturbed. This phenotype was ameliorated in hemizygote PA-DV KI mice, indicating that excess Reelin signaling is detrimental to hippocampal layer formation. The neuronal dendrites of PA-DV KI mice had more branches and were elongated compared to wild-type mice. These results present the first direct evidence of the physiological importance of Reelin cleavage.Reelin is a large secreted glycoprotein that regulates many important events in mammalian brain development 1-3 . It is also involved in synaptic plasticity and the modulation of higher brain functions 1,4-8 . At the cellular level, Reelin induces the clustering of apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which is the prerequisite for the phosphorylation of the cytosolic adaptor protein Dab1 9-11 . Phosphorylated Dab1 is quickly degraded 1,2,5 . Thus, the amount of Dab1 is indicative of the strength of Reelin signaling [12][13][14][15] . Several pathways act downstream of Dab1 phosphorylation and regulate the cytoskeleton, adhesion molecules, ion channels, and neurotransmitter release 1-3,5,16 . Accordingly, insufficient Reelin signaling could contribute to the pathogenesis of neuropsychiatric disorders, such as epilepsy 17-19 , schizophrenia 6,16,20 , and autism 3,8,16 . Furthermore, recent studies showed that a decrease or insufficiency in Reelin signaling could aggravate Alzheimer's disease (AD) 13,21-26 . Therefore, it is important to understand the molecular mechanisms by which Reelin is regulated. Of particular importance is understanding how Reelin signaling is turned off because inhibition of such a mechanism would strengthen Reelin signaling and may help improve brain disorders caused by diminished Reelin function.Secreted signaling proteins can be inactivated or disabled by a variety of mechanisms, including internalization by its receptor, sequestration by an inactive (decoy) binding partner, and degradation. Internalization via ApoER2 and VLDLR 27,28 and a dominant-negative effect of the secreted extracellular domain of ApoER2 29 play a role in limiting Reelin signaling. Reelin protein (approximately 430 kDa as a monomer) contains three specific cleavage sites (N-t, C-t, and WC; reviewed in 7 ). N-t cleavage occurs between Pro1244 and Ala1245 to generate two fragments with molecular mas...

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“…It is also involved in synaptic plasticity and the modulation of higher brain functions 1,[4][5][6][7][8] . At the cellular level, Reelin induces the clustering of apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which is the prerequisite for the phosphorylation of the cytosolic adaptor protein Dab1 [9][10][11] . Phosphorylated Dab1 is quickly degraded 1,2,5 .…”

Section: Introductionmentioning

confidence: 99%

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Okugawa

Ogino

Shigenobu

et al. 2020

Preprint

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Reelin is a secreted protein that plays versatile roles in neuronal development and function, and hypoactivity of Reelin is implicated in many neuropsychiatric disorders. The strength of Reelin signaling is regulated by proteolytic processing, but its importance in vivo is not yet fully understood. Here, we generated Reelin knock-in (PA-DV KI) mice in which the key cleavage site of Reelin was abolished by mutation. As expected, the cleavage of Reelin was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice. The amount of Dab1, whose degradation is induced by Reelin signaling, decreased in these tissues, indicating that the signaling strength of Reelin was augmented. The brains of PA-DV KI mice were largely structurally normal, but unexpectedly, the hippocampal layer was disturbed. This phenotype was ameliorated in hemizygote PA-DV KI mice, indicating that excess Reelin signaling is detrimental to hippocampal layer formation. The neuronal dendrites of PA-DV KI mice had more branches and were elongated compared to wild-type mice. These results present the first direct evidence of the physiological importance of Reelin cleavage and suggest that inhibition of Reelin cleavage would counteract neuropsychiatric disorders without causing severe systemic side effects.

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The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease

Cited by 75 publications

References 89 publications

LRP8 is overexpressed in estrogen‐negative breast cancers and a potential target for these tumors

LRP8 is overexpressed in estrogen‐negative breast cancers and a potential target for these tumors

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

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