α2-Macroglobulin as a β-amyloid peptide-binding plasma protein

Yansheng Du, Binhui Ni, Michele Glinn, Richard C. Dodel, Kelly R. Bales, Zhiyuan Zhang, Paul A. Hyslop, Steven M. Paul

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

The β-amyloid peptide (Aβ) is a normal proteolytic processing product of the amyloid precursor protein, which is constitutively expressed by many, if not most, cells. For reasons that are still unclear, Aβ is deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease (AD). The factor(s) responsible for the clearance of soluble Aβ from biological fluids or tissues are poorly understood. We now report that human α2-macroglobulin (α2M), a major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds 125I-Aβ((1-42)) with high affinity (apparent dissociation constant of 3.8 x 10-10 M). Approximately 1 mol of Aβ is bound per mole of α2M. Both native and methylamine-activated α2M bind 125I-Aβ((1-42)). The binding of 125I-Aβ((1-42)) to α2M is enhanced by micromolar concentrations of Zn2+ (but not Ca2+) and is inhibited by noniodinated Aβ((1-42)) and Aβ((1-40)) but not by the reverse peptide Aβ((40-1)) or the cytokines interleukin 1β or interleukin 2. α1- Antichymotrypsin, another plaque-associated protein, inhibits both the binding of 125I-Aβ((1-42)) to α2M as well as the degradation of 125I-Aβ((1-42)) by proteinase-activated α2M. Moreover, the binding of 125I-Aβ((1-42)) to α2M protects the peptide from proteolysis by exogenous trypsin. These data suggest that α2M may function as a carrier protein for Aβ and could serve to either facilitate or impede clearance of Aβ from tissues such as the brain.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalJournal of Neurochemistry
Volume69
Issue number1
DOIs
StatePublished - Jul 1997

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Brain
  • Senile plaques
  • α-Macroglobulin
  • β-Amyloid peptide

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Du, Y., Ni, B., Glinn, M., Dodel, R. C., Bales, K. R., Zhang, Z., Hyslop, P. A., & Paul, S. M. (1997). α2-Macroglobulin as a β-amyloid peptide-binding plasma protein. Journal of Neurochemistry, 69(1), 299-305. https://doi.org/10.1046/j.1471-4159.1997.69010299.x