Skip to main content
SpringerLink
Log in

The βA4 Amyloid Peptide Enhances Cellular Uptake of Apolipoprotein E-Containing Lipoproteins by the Low-Density Lipoprotein Receptor-Related Protein/α 2-Macroglobulin Receptor

  • Conference paper
Book cover Apolipoprotein E and Alzheimer’s Disease

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

  • 90 Accesses

Summary

We incubated β-very low density lipoprotein (β-VLDL) from cholesterol-fed rabbits with βA4 amyloid peptide (43mer). βA4 associated with the apolipoprotein E moiety of the βVLDL. The binding of βA4 to apolipoprotein E could not be dissociated with sodium dodecyl sulphate. Unlike native βVLDL, the βA4/βVLDL complexes bound to the low-density lipoprotein (LDL) receptor-related protein of normal and familial hypercholesterolemia fibroblasts in culture. The βA/βVLDL complexes were taken up into the cells, but escaped proteolytic degradation. The cellular uptake of βA4/βVLDL com plexes was independent from the LDL receptor pathway; it was inhibited by an excess of unlabelled, activated α 2-macroglobulin. βA4 competed with the binding and the uptake, but not the degradation, of 125I-labelled α 2-macroglobulin in fibroblasts. Considered together, the data suggest that the association of βA4 with apolipoprotein E-containing lipoproteins gives rise to complexes that are endocytosed through the LDL receptor-related protein but fails to undergo proteolytic degradation in the lysosomes. These findings may be relevant to the pathobiochemistry of Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Ashcom JD, Tiller SE, Dickerson K, Cravens JL, Argraves WS, Strickland DK (1990) The human α2-macroglobulin receptor: Identification of a 420-kD cell surface glycoprotein specific for the activated conformation of α2 macroglobulin. J Cell Biol 110: 1041–1048

    Article  PubMed  CAS  Google Scholar 

  • Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Volk B, Berger M (1991) Interleukin-6 and α2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett 285: 111–114

    Article  PubMed  CAS  Google Scholar 

  • Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76: 1501–1513

    Article  PubMed  CAS  Google Scholar 

  • Boyles JK, Zoellner CD, Anderson LJ, Kosik LM, Pitas RE, Weisgraber KH, Hui DY, Mahley RW, Gebicke-Haerter PJ, Ignatius MJ, Shooter EM (1989) A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport. J Clin Invest 83: 1015–1031

    Article  PubMed  CAS  Google Scholar 

  • Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8: 1–21

    Article  PubMed  CAS  Google Scholar 

  • Goldstein JL, Basu SK, Brown MS (1983) Receptor-mediated endocytosis of low-density lipopro tein in cultured cells. In: Fleischer S, Fleischer B (eds) Biomembranes. Part L. Membrane biogenesis. Methods in enzymology, Vol 98. Academic Press, Orlando, pp 241–260

    Chapter  Google Scholar 

  • Han SH, Einstein G, Weisgraber KH, Strittmatter WJ, Saunders A, Pericak-Vance M, Roses AD, Schmechel DE (1994) Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J Neuropathol Exp Neurol 53: 535–544

    Article  PubMed  CAS  Google Scholar 

  • Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK (1988) Surface location and high affinity for calcium of a 500 kD liver membrane protein closely related to the LDL receptor suggest a physiological role as lipoprotein receptor. EMBO J 7: 4119–4127

    PubMed  CAS  Google Scholar 

  • Herz J, Kowal RC, Ho JK, Brown MS, Goldstein JL (1990) Low density lipoprotein receptorrelated protein mediates endocytosis of monoclonal antibodies in cultured cells and in rabbit liver. J Biol Chem 265: 21355–21362

    PubMed  CAS  Google Scholar 

  • Hussain MM, Maxfield FR, Mäs-Oliva J, Tabas I, Ji Z-S, Innerarity TL, Mahley RW (1991) Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/ (x2-macroglobulin receptor. J Biol Chem 226: 13936–13940

    Google Scholar 

  • Ignatius MJ, Gebicke-Haerter PJ, Skene JHP, Schilling JW, Weisgraber KH, Mahley RW, Shooter EM (1986) Expression of apolipoprotein E during nerve degeneration and regen eration. Proc Natl Acad Sci USA 83: 1125–1129

    Article  PubMed  CAS  Google Scholar 

  • Kovanen PT, Brown MS, Basu SK, Bilheimer DW, Goldstein JL (1981) Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. Proc Natl Acad Sci USA 78: 1396–1400

    Article  PubMed  CAS  Google Scholar 

  • Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS (1989) Low density lipoprotein receptorrelated protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci USA 86: 5810–5814

    Article  PubMed  CAS  Google Scholar 

  • Krieger M, Herz J (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor related-protein (LRP). Annu Rev Biochem 63: 601–637

    Article  PubMed  CAS  Google Scholar 

  • Kristensen T, Moestrup SK, Glieman J, Bendtsen L, Sand O, Sottrup-Jensen L (1990) Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the α2 macroglobulin receptor. FEBS Lett 276: 151–155

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 227: 680–685

    Article  PubMed  CAS  Google Scholar 

  • Mahley RW (1988) Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science 240: 622–630

    Article  PubMed  CAS  Google Scholar 

  • März W, Beckmann A, Scharnagl H, Siekmeier R, Mondorf U, Held I, Schneider W, Preissner KT, Curtiss LK, Groß W, Hüttinger M (1993a) Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/L2-macroglobulin. FEBS Lett 325: 271–275

    Article  PubMed  Google Scholar 

  • März W, Baumstark MW, Scharnagl H, Ruzicka V, Buxbaum S, Herwig J, Pohl T, Russ A, Schaaf L, Berg A, Böhles H-J, Usadel KH, Groß W (1993b) Accumulation of “small dense” low density lipoproteins in a homozygous patient with familial defective apolipoprotein B-100 results from heterogeneous interaction of LDL-subfractions with the LDL receptor. J Clin Invest 92: 2922–2933

    Article  PubMed  Google Scholar 

  • Namba Y, Tomonaga M, Kawasaki H, Otomo EKI (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeld-Jakob disease. Brain Res 541: 163–166

    Article  PubMed  CAS  Google Scholar 

  • Ohm TG, Kirca M, Bohl J, Scharnagl H, Groß W, März W (1995) ApoE influences not only cerebral senile plaque load, but also Alzheimer-type neurofibrillary tangles. Neuroscience 66: 583–587

    Article  PubMed  CAS  Google Scholar 

  • Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342: 697–699

    Article  PubMed  CAS  Google Scholar 

  • Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apoliporotein E in sporadic Alzheimer’s disease: Allelic variation and receptor interactions. Neuron 11: 575–580

    Article  PubMed  CAS  Google Scholar 

  • Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele 1–4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472

    PubMed  CAS  Google Scholar 

  • Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid ß-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 9649–9653

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53: 438–447

    Article  PubMed  CAS  Google Scholar 

  • Sinn HJ, Schrenk HH, Friedrich EA, Via DP, Dresel HA (1988) Radioiodination of proteins and lipoproteins using n-bromosuccinimide as oxidizing reagent. Anal Biochem 170: 186–192

    Article  PubMed  CAS  Google Scholar 

  • Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS (1990) Se quence identity between the α2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 265: 17401–17404

    PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesan GS, Roses AD (1993a) Apolipoprotein E: high-avidity binding to ß-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981

    Article  PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Huang DY, Dong L-M, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993b) Binding of human apolipoprotein E to synthetic amyloid ß peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 8098–8102

    Article  PubMed  CAS  Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder EH, Dong L-M, Jakes R, Alberts MJ, Gilbert JR, Schmechel DE, Pericak-Vance MA, Roses AD (1994) Hypothesis: microtubule instability and paired helical filament formation in Alzheimer disease brain as a function of apolipoprotein E genotype. Exp Neurol 125: 163–171

    Article  PubMed  CAS  Google Scholar 

  • Utermann G (1987) Apolipoprotein E polymorphism in health and disease. Am Heart J 113: 433–440

    Article  PubMed  CAS  Google Scholar 

  • Weisgraber KH, Rail SC, Mahley RW (1981) Human E apoprotein heterogeneity. Cysteine arginine interchanges in the amino acid sequence of the apoE isoforms. J Biol Chem 256: 9077–9083

    PubMed  CAS  Google Scholar 

  • Willnow TE, Goldstein JL, Orth K, Brown MS, Herz J (1992) Low density lipoprotein receptorrelated protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem 267: 26172–26180

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Chemistry, Department of Medicine, Albert-Ludwigs University, Hugstetter Strasse 55, 70106, Freiburg, Germany

    H. Scharnagl

Authors
  1. H. Scharnagl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Winkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hüttinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Wittmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Nauck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Wieland
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. Groß
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T. G. Ohm
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W. März
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Joseph and Kathleen Bryan Alzheimer’s Disease Research Center Departments of Medicine (Neurology) and Neurobiology, Duke University Medical Center, P.O. Box 2900, Durham, NC, 27710, USA

    A. D. Roses M.D.

  2. Gladstone Institute of Cardiovascular Disease Department of Pathology, Cardiovascular Research Institute, University of California, San Francisco, CA, 94141-9100, USA

    K. Weisgraber M.D.

  3. Fondation IPSEN, 24, rue Erlanger, 75781, Paris, France

    Y. Christen Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Scharnagl, H. et al. (1996). The βA4 Amyloid Peptide Enhances Cellular Uptake of Apolipoprotein E-Containing Lipoproteins by the Low-Density Lipoprotein Receptor-Related Protein/α 2-Macroglobulin Receptor. In: Roses, A.D., Weisgraber, K., Christen, Y. (eds) Apolipoprotein E and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-80109-9_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-80109-9_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-80111-2

  • Online ISBN: 978-3-642-80109-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation