Point Substitution in the Central Hydrophobic Cluster of a Human β-Amyloid Congener Disrupts Peptide Folding and Abolishes Plaque Competence

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Abstract
Alzheimer's disease (AD) is pathologically characterized by the presence of numerous insoluble amyloid plaques in the brain composed primarily of a 40−43 amino acid peptide, the human β-amyloid peptide (Aβ). The process of Aβ deposition can be modeled in vitro by deposition of physiological concentrations of radiolabeled Aβ onto preexisting amyloid in preparations of unfixed AD cerebral cortex. Using this model system, it has been shown that Aβ deposition is biochemically distinct from Aβ aggregation and occurs readily at physiological Aβ concentrations, but which regions and conformations of Aβ are essential to Aβ deposition is poorly understood. We report here that an active congener, Aβ(10−35)-NH2, displays time dependence, pH−activity profile, and kinetic order of deposition similar to Aβ(1−40), and is sufficiently soluble for NMR spectroscopy in water under conditions where it actively deposits. To examine the importance of the central hydrophobic cluster of Aβ (LVFFA, residues 17−21) for in vitro Aβ deposition, an Aβ(10−35)-NH2 analog with a single point substitution (F19T) in this region was synthesized and examined. Unlike Aβ(10−35)-NH2, the F19T analog was plaque growth incompetent, and NMR analysis indicated that the mutant peptide was significantly less folded than wild-type Aβ. These results support previous studies suggesting that the plaque competence of Aβ correlates with peptide folding. Since compounds that alter Aβ folding may reduce amyloid deposition, the central hydrophobic cluster of Aβ will be a tempting target for structure-based drug design when high-resolution structural information becomes available.