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α2‐Macroglobulin Complexes with and Mediates the Endocytosis of β‐Amyloid Peptide via Cell Surface Low‐Density Lipoprotein Receptor‐Related Protein

Narita, Masaaki, Holtzman, David M., Schwartz, Alan L., Bu, Guojun·1997·Journal of Neurochemistry
DOI 10.1046/j.1471-4159.1997.69051904.x
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Abstract

Abstract: A primary histopathological feature of Alzheimer's disease is the accumulation of β‐amyloid (Aβ) in the brain of afflicted individuals. However, Aβ is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that Aβ forms stable complexes with activated α 2‐macroglobulin (α 2 M⋆), a physiological ligand for the low‐density lipoprotein receptor‐related protein (LRP) that is abundantly expressed in the CNS. These α 2 M⋆/125 I‐Aβ complexes are immunoreactive with both anti‐Aβ and anti‐α 2 M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that α 2 M⋆/125 I‐Aβ complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor‐associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125 I‐Aβ is not inhibited by RAP and thus must be mediated via an LRP‐independent pathway. These results suggest that LRP can function as a clearance receptor for Aβ via a physiological ligand.

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Research works printed but not linked: 8

  1. Beisiegel U., Weber W., and Bengtsson-Olivecrona G. (1991) Lipo- protein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc. Nat!. Acad. Sci. USA 88, 8342-8346.
  2. Cataldo A. M. and Nixon R. A. (1990) Enzymatically active lyso- somal proteases are associated with amyloid deposits in Alzhei- mer brain. Proc. Natl. Acad. Sci. USA 87, 3861-3865.
  3. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., and Pen- cak-Vance M. A. (1993) Apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921 -923.
  4. Eriksson S., Janciauskiene S., and Lannfelt L. (1995) a 1-Antichy- motrypsin regulates Alzheimer /I-amyloid peptide fibril forma- tion. Proc. Nat!. Acad. Sci. USA 92, 2313-2317.
  5. Holtzman D. M., Pitas R. E., Kilbridge J., Nathan B., Mahley R. W., Bu G., and Schwartz A. L. (1995) LRP mediates apolipoprotein E-dependent neurite outgrowth in a CNS-derived neuronal cell line. Proc. Nat!. Acad. Sci. USA 92, 9480-9484.
  6. Saito A., Pietromonaco S., Lou A. K-C., and Farquhar M. G. (1994) Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proc. Nat!. Acad. Sci. USA 91, 9725-9729.
  7. J. Neurochem., Vol. 69, No. 5, 1997 14714159, 1997, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1997.69051904.x by Mount Vernon Nazarene University, Wiley Online Library on [29/04/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License · DOI
  8. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., and Roses A. D. (1993) Apoli- poprotein E: high avidity binding to /I-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer dis- ease. Proc. Nat!. Acad. Sci. USA 90, 1977-1981.

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Metadata

Authors
Narita, M., Holtzman, D. M., Schwartz, A. L., & Bu, G.
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
1997-11
Volume
69
Issue
5
Pages
1904-1911
ISSN
  • 0022-3042
  • 1471-4159
DOI
10.1046/j.1471-4159.1997.69051904.x
Cited by
204
References
0
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1843 d)

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