Inhibition of α2-macroglobulin/proteinase-mediated degradation of amyloid β peptide by apolipoprotein E and α1-antichymotrypsin: Evidence that the α2-macroglobulin/proteinase complex mediates degradation of the Aβ peptide

Zhiyuan Zhang, Gary J. Drzewiecki, Patrick C. May, Russell E. Rydel, Steven M. Paul, Paul A. Hyslop

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The soluble amyloid β-peptide (Aβ), is produced from the amyloid β-protein precursor (AβPP) during normal cellular metabolism. The accumulation and deposition of extracellular Aβ in senile plaques, a characteristic neuropathological feature of Alzheimer's disease (AD), may occur as a result of increased Aβ synthesis or decreased degradation/clearance, or both. We now report that trypsin-activated α2-macroglobulin (α2M-T), efficiently degrades Aβ in vitro. Moreover, incubation of Aβ with α2M-T prevents the in vitro formation of Thioflavine-S positive Aβ fibrils as well as Aβ-induced toxicity of cultured human cortical neuronal (HCN-IA) cells. Two senile plaque-associated proteins, apolipoprotein E (apoE) and α1-antichymotrypsin (ACT), markedly inhibit α2M-T-mediated Aβ degradation by a process that does not involve inhibition of the α2M-T catalytic site. Thus, the degradation and clearance of Aβ by α2M-T may be impaired by the amyloid-promoting factors, apoE and ACT, both of which have been shown to be elevated in AD brain and to be possible genetic risk factors for AD.

Original languageEnglish
Pages (from-to)156-161
Number of pages6
JournalAmyloid
Volume3
Issue number3
DOIs
StatePublished - 1996

Keywords

  • Aβ clearance
  • Proteolytic degradation
  • α-macroglobulin

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