Home LiteratureArticle Details
PMID: 12411487 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing.

The EMBO journal ·Vol. 21 ·No. 21 ·2002-11-01 ·Pages 5691-700

Pietrzik CU, Busse T, Merriam DE, Weggen S, Koo EH

Abstract

The low-density lipoprotein receptor-related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the beta-amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid beta-protein (Abeta). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Abeta production, APP secretion, APP internalization, turnover of full-length APP and stability of APP C-terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504-4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Abeta production, through interactions of the cytosolic domains.

MeSH Terms
Amyloid beta-Protein Precursor/metabolism Animals Blotting, Western Cell Line Cytoplasm/metabolism DNA, Complementary Enzyme-Linked Immunosorbent Assay Fibroblasts/metabolism Low Density Lipoprotein Receptor-Related Protein-1/chemistry,genetics,physiology Mice Precipitin Tests Protein Processing, Post-Translational
Chemicals
Amyloid beta-Protein Precursor DNA, Complementary Low Density Lipoprotein Receptor-Related Protein-1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Pietrzik Claus U
Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA.
Busse Tracy
Merriam David E
Weggen Sascha
Koo Edward H
References (43)
43 references, click to expand
  1. RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors.
    EMBO J. 1996 Jun 3;15(11):2632-9 PMID: 8654360
  2. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line.
    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9480-4 PMID: 7568158
  3. Receptor-associated protein is a folding chaperone for low density lipoprotein receptor-related protein.
    J Biol Chem. 1996 Sep 6;271(36):22218-24 PMID: 8703036
  4. Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP).
    Brain Res. 1996 Nov 18;740(1-2):6-14 PMID: 8973792
  5. Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling.
    J Neurosci. 1997 Jan 1;17(1):140-51 PMID: 8987743
  6. Molecular analysis of ligand binding to the second cluster of complement-type repeats of the low density lipoprotein receptor-related protein. Evidence for an allosteric component in receptor-associated protein-mediated inhibition of ligand binding.
    J Biol Chem. 1997 May 23;272(21):13608-13 PMID: 9153209
  7. Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides.
    Nat Med. 1997 Sep;3(9):1016-20 PMID: 9288729
  8. Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.
    Nat Med. 1997 Sep;3(9):1021-3 PMID: 9288730
  9. Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein.
    J Neurochem. 1997 Nov;69(5):1904-11 PMID: 9349534
  10. Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture.
    J Cell Biol. 1998 May 18;141(4):1031-9 PMID: 9585420
  11. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein.
    J Biol Chem. 1998 Dec 11;273(50):33556-60 PMID: 9837937
  12. Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42.
    J Biol Chem. 1999 Jul 2;274(27):18851-6 PMID: 10383380
  13. Rab15 mediates an early endocytic event in Chinese hamster ovary cells.
    J Biol Chem. 1999 Aug 6;274(32):22303-12 PMID: 10428799
  14. Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons.
    J Cell Biol. 1999 Oct 18;147(2):277-94 PMID: 10525535
  15. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
    Science. 1999 Oct 22;286(5440):735-41 PMID: 10531052
  16. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.
    Neuron. 1999 Oct;24(2):481-9 PMID: 10571241
  17. Identification of a novel aspartic protease (Asp 2) as beta-secretase.
    Mol Cell Neurosci. 1999 Dec;14(6):419-27 PMID: 10656250
  18. Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease.
    J Biol Chem. 2000 Mar 10;275(10):7410-5 PMID: 10702315
  19. Proteolytic processing and cell biological functions of the amyloid precursor protein.
    J Cell Sci. 2000 Jun;113 ( Pt 11):1857-70 PMID: 10806097
  20. Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease.
    Arch Neurol. 2000 May;57(5):646-50 PMID: 10815129
  21. The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein.
    J Biol Chem. 2000 Jun 2;275(22):17187-94 PMID: 10747918
  22. Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.
    J Clin Invest. 2000 Nov;106(9):1159-66 PMID: 11067868
  23. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier.
    J Clin Invest. 2000 Dec;106(12):1489-99 PMID: 11120756
  24. Association of membrane-bound amyloid precursor protein APP with the apolipoprotein E receptor LRP.
    Brain Res Mol Brain Res. 2001 Mar 5;87(2):238-45 PMID: 11245926
  25. Apolipoprotein E receptors: linking brain development and Alzheimer's disease.
    Nat Rev Neurosci. 2000 Oct;1(1):51-8 PMID: 11252768
  26. The LDL receptor gene family: (un)expected signal transducers in the brain.
    Neuron. 2001 Mar;29(3):571-81 PMID: 11301018
  27. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60.
    Science. 2001 Jul 6;293(5527):115-20 PMID: 11441186
  28. The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.
    J Biol Chem. 2001 Sep 28;276(39):36788-96 PMID: 11466313
  29. Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65.
    J Neurosci. 2001 Nov 1;21(21):8354-61 PMID: 11606623
  30. Low-density lipoprotein receptor family: endocytosis and signal transduction.
    Mol Neurobiol. 2001 Feb;23(1):53-67 PMID: 11642543
  31. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function betwenn LRP and the PDGF.
    J Biol Chem. 2002 May 3;277(18):15499-506 PMID: 11854294
  32. Platelet-derived growth factor mediates tyrosine phosphorylation of the cytoplasmic domain of the low Density lipoprotein receptor-related protein in caveolae.
    J Biol Chem. 2002 May 3;277(18):15507-13 PMID: 11854295
  33. Proteolytic processing of low density lipoprotein receptor-related protein mediates regulated release of its intracellular domain.
    J Biol Chem. 2002 May 24;277(21):18736-43 PMID: 11907044
  34. Cohort movement of different ligands and receptors in the intracellular endocytic pathway of alveolar macrophages.
    J Biol Chem. 1989 May 15;264(14):8164-70 PMID: 2470742
  35. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.
    Nucleic Acids Res. 1990 Jun 25;18(12):3587-96 PMID: 2194165
  36. Low density lipoprotein receptor-related protein mediates endocytosis of monoclonal antibodies in cultured cells and rabbit liver.
    J Biol Chem. 1990 Dec 5;265(34):21355-62 PMID: 2250029
  37. Alpha 2-macroglobulin-proteinase complexes, plasminogen activator inhibitor type-1-plasminogen activator complexes, and receptor-associated protein bind to a region of the alpha 2-macroglobulin receptor containing a cluster of eight complement-type repeats.
    J Biol Chem. 1993 Jun 25;268(18):13691-6 PMID: 7685767
  38. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system.
    J Neurosci. 1993 Jul;13(7):3136-42 PMID: 8331390
  39. Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein.
    J Biol Chem. 1994 Jun 3;269(22):15827-32 PMID: 7515061
  40. Evidence that production and release of amyloid beta-protein involves the endocytic pathway.
    J Biol Chem. 1994 Jul 1;269(26):17386-9 PMID: 8021238
  41. Pseudomonas exotoxin-mediated selection yields cells with altered expression of low-density lipoprotein receptor-related protein.
    J Cell Biol. 1995 Jun;129(6):1533-41 PMID: 7790352
  42. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation.
    Cell. 1995 Jul 28;82(2):331-40 PMID: 7543026
  43. Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody.
    J Cell Sci. 1996 May;109 ( Pt 5):991-8 PMID: 8743946
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf568
Published
2002-11-01
Pages
5691-700
Language
English
Region
England
NLM ID
8208664
PMCID
PMC131065
Subset
IM
Grants
NIA NIH HHS · R01 AG012376 · United States
NIA NIH HHS · AG12376 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdf568 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2