CoChat
Sign Up
Cited by 430Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsDrug Transport and Resistance Mechanisms

Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers.

Open access
Zlokovic, B V, Martel, C L, Matsubara, E, McComb, J G, Zheng, G, McCluskey, R T, Frangione, B, Ghiso, J·1996·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.93.9.4229PMC PMC39517
Open this paper in CoChat — free account

Abstract

A soluble form of Alzheimer disease amyloid beta-protein (sA beta) is transported in the blood and cerebrospinal fluid mainly complexed with apolipoprotein J (apoJ). Using a well-characterized in situ perfused guinea pig brain model, we recently obtained preliminary evidence that apoJ facilitates transport of sA beta (1-40)-apoJ complexes across the blood-brain barrier and the blood-cerebrospinal fluid barrier, but the mechanisms remain poorly understood. In the present study, we examined the transport process in greater detail and investigated the possible role of glycoprotein 330 (gp330)/megalin, a receptor for multiple ligands, including apoJ. High-affinity transport systems with a Km of 0.2 and 0.5 nM were demonstrated for apoJ at the blood-brain barrier and the choroid epithelium in vivo, suggesting a specific receptor-mediated mechanism. The sA beta (1-40)-apoJ complex shared the same transport mechanism and exhibited 2.4- to 10.2-fold higher affinity than apoJ itself. Binding to microvessels, transport into brain parenchyma, and choroidal uptake of both apoJ and sA beta (1-40)-apoJ complexes were markedly inhibited (74-99%) in the presence of a monoclonal antibody to gp330/megalin and were virtually abolished by perfusion with the receptor-associated protein, which blocks binding of all known ligands to gp330. Western blot analysis of cerebral microvessels with the monoclonal antibody to gp330 revealed a protein with a mass identical to that in extracts of kidney membranes enriched with gp330/megalin, but in much lower concentration. The findings suggest that gp330/megalin mediates cellular uptake and transport of apoJ and sA beta (1-40)-apoJ complex at the cerebral vascular endothelium and choroid epithelium.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.93.9.4229

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • APOJ or clusterin (CLU) binds to LRP2 (or megalin) at the blood-brain barrier, which mediates Aβ42 transport from brain to blood.

    “Additionally, APOJ or clusterin (CLU) binds to LRP2 (or megalin) at the BBB, which mediates A 𝛃 42 transport from brain to blood (58, 700).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [700]

    The study passage supports a role for gp330/megalin in apoJ binding and transport at the blood–brain barrier. It examines Aβ(1–40)–apoJ transport into brain parenchyma, not Aβ42 transport from brain to blood; the latter direction and peptide are not supported by this source. The indexed passage provides no section or page label. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • LRP2 also known as glycoprotein 330 or megalin mediates transport of Aβ-clusterin complexes across the BBB.

    “LRP2 also known as glycoprotein 330 (gp330) or megalin mediates transport of A 𝛃 -clusterin complexes across the BBB (58, 700).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [700]

    The paper’s summary (pp. 4229–4234) reports that blocking gp330/megalin markedly inhibited transport of amyloid-β(1–40)–apoJ (clusterin) complexes in a guinea pig brain model. It concludes that gp330/megalin *may* mediate transport at the cerebral vascular endothelium; the citing sentence presents that proposed mechanism as established. The supplied copy also does not use the name LRP2. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 34

  1. Abbate M., Bachinsky D., Zheng G., Stamenkovic I., McLaughlin M., Niles J. L., McCluskey R. T., Brown D. Location of gp330/alpha 2-m receptor-associated protein (alpha 2-MRAP) and its binding sites in kidney: distribution of endogenous alpha 2-MRAP is modified by tissue processing. Eur J Cell Biol. 1993 Jun;61(1):139–149. [PubMed] [Google Scholar]
  2. Bachinsky D. R., Zheng G., Niles J. L., McLaughlin M., Abbate M., Andres G., Brown D., McCluskey R. T. Detection of two forms of GP330. Their role in Heymann nephritis. Am J Pathol. 1993 Aug;143(2):598–611. [PMC free article] [PubMed] [Google Scholar]
  3. Farquhar M. G., Saito A., Kerjaschki D., Orlando R. A. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol. 1995 Jul;6(1):35–47. doi: 10.1681/ASN.V6135. [DOI] [PubMed] [Google Scholar] · DOI
  4. Farquhar M. G. The unfolding story of megalin (gp330): now recognized as a drug receptor. J Clin Invest. 1995 Sep;96(3):1184–1184. doi: 10.1172/JCI118149. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. Ghiso J., Matsubara E., Koudinov A., Choi-Miura N. H., Tomita M., Wisniewski T., Frangione B. The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem J. 1993 Jul 1;293(Pt 1):27–30. doi: 10.1042/bj2930027. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  6. Ghiso J., Wisniewski T., Frangione B. Unifying features of systemic and cerebral amyloidosis. Mol Neurobiol. 1994 Feb;8(1):49–64. doi: 10.1007/BF02778007. [DOI] [PubMed] [Google Scholar] · DOI
  7. Glass C. K., Pittman R. C., Keller G. A., Steinberg D. Tissue sites of degradation of apoprotein A-I in the rat. J Biol Chem. 1983 Jun 10;258(11):7161–7167. [PubMed] [Google Scholar]
  8. Herz J., Goldstein J. L., Strickland D. K., Ho Y. K., Brown M. S. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991 Nov 5;266(31):21232–21238. [PubMed] [Google Scholar]
  9. Jenne D. E., Tschopp J. Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem Sci. 1992 Apr;17(4):154–159. doi: 10.1016/0968-0004(92)90325-4. [DOI] [PubMed] [Google Scholar] · DOI
  10. Kerjaschki D., Farquhar M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med. 1983 Feb 1;157(2):667–686. doi: 10.1084/jem.157.2.667. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. Kerjaschki D., Horvat R., Binder S., Susani M., Dekan G., Ojha P. P., Hillemanns P., Ulrich W., Donini U. Identification of a 400-kd protein in the brush borders of human kidney tubules that is similar to gp330, the nephritogenic antigen of rat Heymann nephritis. Am J Pathol. 1987 Oct;129(1):183–191. [PMC free article] [PubMed] [Google Scholar]
  12. Kerjaschki D., Miettinen A., Farquhar M. G. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane. J Exp Med. 1987 Jul 1;166(1):109–128. doi: 10.1084/jem.166.1.109. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  13. Koudinov A., Matsubara E., Frangione B., Ghiso J. The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma. Biochem Biophys Res Commun. 1994 Dec 15;205(2):1164–1171. doi: 10.1006/bbrc.1994.2788. [DOI] [PubMed] [Google Scholar] · DOI
  14. Kounnas M. Z., Chappell D. A., Strickland D. K., Argraves W. S. Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro. J Biol Chem. 1993 Jul 5;268(19):14176–14181. [PubMed] [Google Scholar]
  15. Kounnas M. Z., Loukinova E. B., Stefansson S., Harmony J. A., Brewer B. H., Strickland D. K., Argraves W. S. Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. J Biol Chem. 1995 Jun 2;270(22):13070–13075. doi: 10.1074/jbc.270.22.13070. [DOI] [PubMed] [Google Scholar] · DOI
  16. Maness L. M., Banks W. A., Podlisny M. B., Selkoe D. J., Kastin A. J. Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci. 1994;55(21):1643–1650. doi: 10.1016/0024-3205(94)00331-9. [DOI] [PubMed] [Google Scholar] · DOI
  17. Matsubara E., Frangione B., Ghiso J. Characterization of apolipoprotein J-Alzheimer's A beta interaction. J Biol Chem. 1995 Mar 31;270(13):7563–7567. doi: 10.1074/jbc.270.13.7563. [DOI] [PubMed] [Google Scholar] · DOI
  18. Matsuo S., Fukatsu A., Taub M. L., Caldwell P. R., Brentjens J. R., Andres G. Glomerulonephritis induced in the rabbit by antiendothelial antibodies. J Clin Invest. 1987 Jun;79(6):1798–1811. doi: 10.1172/JCI113021. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. Moestrup S. K., Cui S., Vorum H., Bregengård C., Bjørn S. E., Norris K., Gliemann J., Christensen E. I. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest. 1995 Sep;96(3):1404–1413. doi: 10.1172/JCI118176. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  20. Moestrup S. K., Nielsen S., Andreasen P., Jørgensen K. E., Nykjaer A., Røigaard H., Gliemann J., Christensen E. I. Epithelial glycoprotein-330 mediates endocytosis of plasminogen activator-plasminogen activator inhibitor type-1 complexes. J Biol Chem. 1993 Aug 5;268(22):16564–16570. [PubMed] [Google Scholar]
  21. Raychowdhury R., Niles J. L., McCluskey R. T., Smith J. A. Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science. 1989 Jun 9;244(4909):1163–1165. doi: 10.1126/science.2786251. [DOI] [PubMed] [Google Scholar] · DOI
  22. Saito A., Pietromonaco S., Loo A. K., Farquhar M. G. Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9725–9729. doi: 10.1073/pnas.91.21.9725. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. Saito Y., Buciak J., Yang J., Pardridge W. M. Vector-mediated delivery of 125I-labeled beta-amyloid peptide A beta 1-40 through the blood-brain barrier and binding to Alzheimer disease amyloid of the A beta 1-40/vector complex. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10227–10231. doi: 10.1073/pnas.92.22.10227. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. Schlosshauer B. The blood-brain barrier: morphology, molecules, and neurothelin. Bioessays. 1993 May;15(5):341–346. doi: 10.1002/bies.950150508. [DOI] [PubMed] [Google Scholar] · DOI
  25. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., Roses A. D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  26. Willnow T. E., Goldstein J. L., Orth K., Brown M. S., Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed] [Google Scholar]
  27. Willnow T. E., Sheng Z., Ishibashi S., Herz J. Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science. 1994 Jun 3;264(5164):1471–1474. doi: 10.1126/science.7515194. [DOI] [PubMed] [Google Scholar] · DOI
  28. Wisniewski T., Ghiso J., Frangione B. Alzheimer's disease and soluble A beta. Neurobiol Aging. 1994 Mar-Apr;15(2):143–152. doi: 10.1016/0197-4580(94)90105-8. [DOI] [PubMed] [Google Scholar] · DOI
  29. Zheng G., Bachinsky D. R., Stamenkovic I., Strickland D. K., Brown D., Andres G., McCluskey R. T. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). J Histochem Cytochem. 1994 Apr;42(4):531–542. doi: 10.1177/42.4.7510321. [DOI] [PubMed] [Google Scholar] · DOI
  30. Zlokovic B. V. Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier. Pharm Res. 1995 Oct;12(10):1395–1406. doi: 10.1023/a:1016254514167. [DOI] [PubMed] [Google Scholar] · DOI
  31. Zlokovic B. V., Ghiso J., Mackic J. B., McComb J. G., Weiss M. H., Frangione B. Blood-brain barrier transport of circulating Alzheimer's amyloid beta. Biochem Biophys Res Commun. 1993 Dec 30;197(3):1034–1040. doi: 10.1006/bbrc.1993.2582. [DOI] [PubMed] [Google Scholar] · DOI
  32. Zlokovic B. V., Mackic J. B., Wang L., McComb J. G., McDonough A. Differential expression of Na,K-ATPase alpha and beta subunit isoforms at the blood-brain barrier and the choroid plexus. J Biol Chem. 1993 Apr 15;268(11):8019–8025. [PubMed] [Google Scholar]
  33. Zlokovic B. V., Martel C. L., Mackic J. B., Matsubara E., Wisniewski T., McComb J. G., Frangione B., Ghiso J. Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid beta. Biochem Biophys Res Commun. 1994 Dec 15;205(2):1431–1437. doi: 10.1006/bbrc.1994.2825. [DOI] [PubMed] [Google Scholar] · DOI
  34. de Silva H. V., Stuart W. D., Duvic C. R., Wetterau J. R., Ray M. J., Ferguson D. G., Albers H. W., Smith W. R., Harmony J. A. A 70-kDa apolipoprotein designated ApoJ is a marker for subclasses of human plasma high density lipoproteins. J Biol Chem. 1990 Aug 5;265(22):13240–13247. [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Zlokovic, B. V., Martel, C. L., Matsubara, E., McComb, J. G., Zheng, G., McCluskey, R. T., Frangione, B., & Ghiso, J.
Affiliations
  • Department of Neurological Surgery, Childrens Hospital, Los Angeles, CA, USA.
  • University of Southern California (US)
  • Children's Hospital Los Angeles (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1996-04-30
Volume
93
Issue
9
Pages
4229-4234
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.93.9.4229
PMC
PMC39517
OpenAlex
W2090710011
Cited by
430
References
5
Citations by year
2026: 5 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 13 · 2020: 18 · 2019: 10 · 2018: 18 · 2017: 10 · 2016: 22 · 2015: 16 · 2014: 10 · 2013: 9 · 2012: 24
FWCI
6.54
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r35ag010953-07)
  • National Institute on Aging (AG10953)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK4630)
  • National Institute of Neurological Disorders and Stroke (NS34467)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
megalin, clusterin, amyloid-beta, receptor-mediated transport, blood-brain barrier, blood-CSF barrier, cerebral microvasculature, receptor-associated protein, Alzheimer's disease
MeSH terms
Amino Acid Sequence, Animals, Antibodies, Blood-Brain Barrier, Brain, Capillary Permeability, Cerebrovascular Circulation, Choroid Plexus, Endothelium, Vascular, Female, Glycoproteins, Guinea Pigs, Iodine Radioisotopes, Kinetics, Male, Membrane Glycoproteins, Microcirculation, Molecular Sequence Data, Peptide Fragments, Receptors, LDL, Blotting, Western, Amyloid beta-Peptides, Molecular Chaperones, Heymann Nephritis Antigenic Complex, Clusterin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review