Mutations that replace aromatic side chains promote aggregation of the Alzheimers Aβ peptide

Anne H. Armstrong, Jermont Chen, Angela Fortner McKoy, Michael H. Hecht

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


The aggregation of polypeptides into amyloid fibrils is associated with a number of human diseases. Because these fibrils-or intermediates on the aggregation pathway-play important roles in the etiology of disease, considerable effort has been expended to understand which features of the amino acid sequence promote aggregation. One feature suspected to direct aggregation is the π-stacking of aromatic residues. Such π-stacking interactions have also been proposed as the targets for various aromatic compounds that are known to inhibit aggregation. In the case of Alzheimers disease, the aromatic side chains Phe19 and Phe20 in the wild-type amyloid beta (Aβ) peptide have been implicated. To explicitly test whether the aromaticity of these side chains plays a role in aggregation, we replaced these two phenylalanine side chains with leucines or isoleucines. These residues have similar sizes and hydrophobicities as Phe but are not capable of π-stacking. Thioflavin-T fluorescence and electron microscopy demonstrate that replacement of residues 19 and 20 by Leu or Ile did not prevent aggregation, but rather enhanced amyloid formation. Further experiments showed that aromatic inhibitors of aggregation are as effective against Ile- and Leu-substituted versions of Aβ42 as they are against wild-type Aβ. These results suggest that aromatic π-stacking interactions are not critical for Aβ aggregation or for the inhibition of Aβ aggregation.

Original languageEnglish (US)
Pages (from-to)4058-4067
Number of pages10
Issue number19
StatePublished - May 17 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry


Dive into the research topics of 'Mutations that replace aromatic side chains promote aggregation of the Alzheimers Aβ peptide'. Together they form a unique fingerprint.

Cite this