Role of Apolipoprotein E Receptors in Regulating the Differential in vivo Neurotrophic Effects of Apolipoprotein E

Veinbergs, Isaac; Uden, Emily Van; Mallory, Margaret; Alford, Michael; McGiffert, Christine; DeTeresa, Richard; Orlando, Robert A.; Masliah, Eliezer

doi:10.1006/exnr.2001.7684

Cited by 34 publications

(26 citation statements)

References 52 publications

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“…Not only may attachment of therapeutic proteins to RAP facilitate their entry into the brain, but also delivery of RAP to the brain might be beneficial by itself. RAP has been shown to rescue neurodegeneration when infused into the lateral ventricle of the brain along with apoE3 (Veinbergs et al, 2001) and plays an important role in blocking the tPA-induced disruption of the BBB (Yepes et al, 2003). RAP has a higher influx transfer constant into the brain than most of the cytokines and neurotrophins that we have studied, and its high percent uptake per gram of brain tissue indicates the presence of an efficient transport system (Pan et al, 1997;Pan et al, 1998;Pan and Kastin, 2003).…”

Section: Discussionmentioning

confidence: 85%

Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier

Pan

Kastin

Zankel

et al. 2004

Journal of Cell Science

135

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IntroductionReceptor-associated protein (RAP) is found mainly in the endoplasmic reticulum. RAP plays a key role in the proper folding and trafficking of members of the low-density lipoprotein (LDL) receptor family within the secretory pathway, including LDL receptor-related protein 1 (LRP1) and LDL receptor-related protein 2 (LRP2, megalin) (Bu et al., 1995). RAP has an apparent molecular mass of 39 kDa in humans and 44 kDa in rats, and binds with low affinity to heparin sulfate (Orlando and Farquhar, 1994;Melman et al., 2001). When administered intravenously, recombinant RAP significantly prolongs the plasma half-life of tissue-type plasminogen activator (tPA), which uses LRP1 as a clearance receptor (Warshawsky et al., 1993). This result indicates that binding of circulating RAP to members of the LDL receptor family can significantly inhibit the clearance of other ligands from the blood.Megalin is expressed primarily in a subset of epithelial cell layers including those lining the renal proximal tubule, thyroid colloid, epididymis, alveolae, brain vasculature, and the ciliary body of the eye (Orlando and Farquhar, 1993; Zheng et al.,

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Section: Discussionmentioning

confidence: 85%

Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier

Pan

Kastin

Zankel

et al. 2004

Journal of Cell Science

135

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“…RAP did not promote neurite outgrowth and decreased LRP expression in neuronal processes, causing a largely somatic distribution after RAP treatment. Our earlier work (13) shows that RAP treatment did not affect the overall levels of LRP in neurons (64). The redistribution of LRP by RAP could also play a role in the ability of RAP to prevent ␣2M* and other ligands from promoting neurite outgrowth via LRP.…”

Section: Discussionmentioning

confidence: 93%

Apolipoprotein E Receptors Mediate Neurite Outgrowth through Activation of p44/42 Mitogen-activated Protein Kinase in Primary Neurons

Qiu

Hyman

Rebeck

2004

Journal of Biological Chemistry

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Several ligands of the endocytic low density lipoprotein receptor-related protein (LRP), such as apoE-containing lipoproteins and activated ␣2-macroglobulin (␣2M*), promote neurite outgrowth, suggesting that LRP may have signaling functions. In this study, we found that the treatment of neurons with ␣2M* significantly increased the individual length (by 71%) and numbers (by 139%) of neurites of primary mouse cortical neurons. These effects were blocked by the LRP antagonist, the receptor-associated protein. We found similar neurite outgrowth with purified apoE3 and a tandem apoE peptide containing only the receptor-binding domain. To investigate the intracellular pathway of the LRP signaling involved in neurite outgrowth, we tested the effects of ␣2M* on the phosphorylation of the mitogen-activated protein (MAP) extracellular signal-regulated kinases 1 and 2 (ERK1/2). We found that 1) phospho-MAP kinase levels were altered within 30 min after treatment with ␣2M*, 2) the MAP kinase inhibitor, PD98059, specifically blocked the ␣2M*-induced neurite outgrowth, 3) manipulating intracellular calcium by BayK or BAPTA altered the neurite outgrowth and associated changes in the phospho-MAP kinase levels, which were blunted by ␣2M*, 4) ␣2M* promoted the phosphorylation of the transcription factor CREB through MAP kinase, and 5) LRP-specific antibodies increased levels of phosphorylated MAP kinase and phosphorylated CREB. The effects of ␣2M*, apoE3, and apoE peptides increased LRP levels in the cortical neurons, whereas LRP receptor-associated protein reduced dendritic LRP expression. These results demonstrate that p44/42 MAP kinase plays an important role in LRP-mediated neurite outgrowth with activation involving the effects on calcium homeostasis and downstream effects involving the activation of gene transcription through CREB.

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“…The line has been maintained by crossing heterozygous transgenic mice with nontransgenic (C57BL /6J ϫ DBA /2) F1 breeders. The generation (Willnow et al, 1995) and f urther characterization (Van Uden et al, 1999a;Veinbergs et al, 2001) of R APϪ/Ϫ mice on a C57BL /6 ϫ 129 hybrid background have also been described. Compared with mice expressing endogenous R AP (R APϩ/ϩ), R APϪ/Ϫ mice were selected because previous studies have shown that it is possible to reduce the levels of LRP and other lipoprotein receptors by 75% by deleting the R AP gene (Willnow et al, 1995;Veinbergs et al, 2001) and because the homozygous LRP knock-out model is lethal (Willnow et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

“…For these experiments, RAPϪ/Ϫ mice were selected because previous studies have shown that it is possible to reduce the levels of LRP and other lipoprotein receptors (Van Uden et al, 1999a;Veinbergs et al, 2001) by deleting the R AP gene and because the homozygous LRP knock-out model is lethal (Willnow et al, 1995).…”

mentioning

confidence: 99%

Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein

Uden¹,

Mallory²,

Veinbergs³

et al. 2002

J. Neurosci.

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The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid ␤-protein (A␤) trafficking into the cell. Specifically, LRP binds secreted A␤ complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of A␤ mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on A␤ deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAPϪ/Ϫ) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAPϪ/Ϫ mice, the amount of amyloid deposited doubled in the hAPP tg/RAPϪ/Ϫ background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against A␤ toxicity and that this receptor might play an integral role in A␤ clearance.

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Role of Apolipoprotein E Receptors in Regulating the Differential in vivo Neurotrophic Effects of Apolipoprotein E

Cited by 34 publications

References 52 publications

Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier

Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier

Apolipoprotein E Receptors Mediate Neurite Outgrowth through Activation of p44/42 Mitogen-activated Protein Kinase in Primary Neurons

Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein

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