Sequence determinants of enhanced amyloidogenicity of Alzheimer Aβ42 peptide relative to Aβ40

Woojin Kim, Michael H. Hecht

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92 Scopus citations

Abstract

Aggregation of proteins into insoluble deposits is associated with a variety of human diseases. In Alzheimer disease, the aggregation of amyloid β (Aβ) peptides is believed to play a key role in pathogenesis. Although the 40-mer (Aβ40) is produced in vivo at higher levels than the 42-mer (Aβ42), senile plaque in diseased brains is composed primarily of Aβ42. Likewise, in vitro, Aβ42 forms fibrils more rapidly than Aβ40. The enhanced amyloidogenicity of Aβ42 could be due simply to its greater length. Alternatively, specific properties of residues Ile and Ala might favor aggregation. To distinguish between these two possibilities, we constructed a library of sequences in which residues 41 and 42 were randomized. The aggregation behavior of the resulting sequences was assessed using a high throughput screen, based on the finding that fusions of Aβ42 to green fluorescence protein (GFP) prevent the folding and fluorescence of GFP, whereas mutations in Aβ42 that disrupt aggregation produce green fluorescent fusions. Correlations between the sequences of Aβ42 mutants and the fluorescence of Aβ42-GFP fusions in vivo were confirmed in vitro through biophysical studies of synthetic 42-residue peptides. The data reveal a strong correlation between aggregation propensity and the hydrophobicity and β-sheet propensities of residues at positions 41 and 42. Moreover, several mutants containing hydrophilic residues and/or β-sheet breakers at positions 41 and/or 42 were less prone to aggregate than Aβ40 wherein these two residues are deleted entirely. Thus, properties of the side chains at positions 41 and 42, rather than length per se, cause Aβ42 to aggregate more readily than Aβ40.

Original languageEnglish (US)
Pages (from-to)35069-35076
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number41
DOIs
StatePublished - Oct 14 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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