Generic hydrophobic residues are sufficient to promote aggregation of the Alzheimer's Abeta42 peptide.

One hundred years ago, Alois Alzheimer observed a relationship between cognitive impairment and the presence of plaque in the brains of patients suffering from the disease that bears his name. The plaque was subsequently shown to be composed primarily of a 42-residue peptide called amyloid beta (Abeta) 42. Despite the importance of Abeta42 aggregation in the molecular etiology of Alzheimer's disease, the amino acid sequence determinants of this process have yet to be elucidated. Although stretches of hydrophobic residues in the C-terminal half of Abeta42 have been implicated, the mechanism by which these residues promote aggregation remains unclear. In particular, it is not known whether the side chains of these hydrophobic residues mediate specific interactions that direct self-assembly or, alternatively, whether hydrophobicity per se at these positions is sufficient to promote aggregation. To distinguish between these two possibilities, we substituted 12 hydrophobic residues in the C-terminal half of Abeta42 with random nonpolar residues. The mutant sequences were screened by using a fusion of Abeta42 to GFP. Because aggregation of Abeta42 prevents folding of the GFP reporter, this screen readily distinguishes aggregating from nonaggregating variants of Abeta42. Application of the screen demonstrated that, despite the presence of 8-12 mutations, all of the sequences aggregated. To confirm these results, several of the mutant sequences were prepared as synthetic peptides and shown to form amyloid fibrils similar to those of WT Abeta42. These findings indicate that hydrophobic stretches in the sequence of Abeta42, rather than specific side chains, are sufficient to promote aggregation.