Oligomerization of β-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types

Aneet K. Sian, Emma R. Frears, Omar M A El-Agnaf, Bhroma P. Patel, Maria F. Manca, Giuliano Siligardi, Rohanah Hussain, Brian M. Austen

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Abstract

A novel ELISA has been developed which detects oligomerization of β-amyloid (Aβ). Oligomerization, fibrillization and neurotoxicity of native Aβ associated with Alzheimer's disease (AD) type has been compared with E32Q Aβ (amyloid β-protein containing residues 1-40 with the native Glu at residue 22 changed to Gln) implicated in Dutch cerebral haemorrhage disease. Solutions of Aβ rapidly yield soluble oligomers in a concentration-dependent manner, which are detected by the ELISA, and by size-exclusion gel chromatography. Conformational changes from disordered to β-sheet occur more slowly than oligomerization, and fibrils are produced after prolonged incubation. The E22Q Aβ oligomerizes, changes conformation and fibrillizes more rapidly than the native form and produces shorter stubbier fibrils. Aged fibrillar preparations of E22Q Aβ are more potent than aged fibrils of native Aβ in inducing apoptotic changes and toxic responses in human neuroblastoma cell lines, whereas low-molecular-mass oligomers in briefly incubated solutions are much less potent. The differences in the rates of oligomerization of the two Aβ forms, their conformational behaviour over a range of pH values, and NMR data reported elsewhere, are consistent with a molecular model of oligomerization in which strands of Aβ monomers initially overcome charge repulsion to form dimers in parallel β-sheet arrangement, stabilized by intramolecular hydrophobic interactions, with amino acids of adjacent chains in register.

Original languageEnglish
Pages (from-to)299-308
Number of pages10
JournalBiochemical Journal
Volume349
Issue number1
DOIs
Publication statusPublished - 1 Jul 2000
Externally publishedYes

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Keywords

  • Apoptosis
  • ELISA
  • Fibril
  • Parallel β-sheet
  • Toxicity

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sian, A. K., Frears, E. R., El-Agnaf, O. M. A., Patel, B. P., Manca, M. F., Siligardi, G., Hussain, R., & Austen, B. M. (2000). Oligomerization of β-amyloid of the Alzheimer's and the Dutch-cerebral-haemorrhage types. Biochemical Journal, 349(1), 299-308. https://doi.org/10.1042/0264-6021:3490299