A conformation change in the carboxyl terminus of Alzheimer's A beta(1-40)accompanies the transition from dimer to fibril as revealed by fluorescence quenching analysis

Alzheimer's disease is characterized by the presence of insoluble, fibrous deposits composed principally of amyloid beta (A beta) peptide. A number of studies have provided information on the fibril structure and on the facto rs affecting fiber formation, but the details of the fibril structure are n ot known. We used fluorescence quenching to investigate the solvent accessi bility and surface charge of the soluble A beta(1-40) dimer and amyloid fib rils, Analogs of A beta(1-40) containing a single tryptophan were synthesiz ed by substituting residues at positions 4, 10, 34, and 40 with tryptophan, Quenching measurements in the dimeric state indicate that the amino-termin al analogs (A beta F4W and A beta Y10W) are accessible to polar quenchers, and the more carboxyl-terminal analog A beta V34W is less accessible. A bet a V40W, on the other hand, exhibits a low degree of quenching, indicating t hat this residue is highly shielded from the solvent in the dimeric state. Correcting for the effect of reduced translational and rotational diffusion , fibril formation was associated with a selective increase in solvent expo sure of residues 34 and 40, suggesting that a conformation change may take place in the carboxyl-terminal region coincident with the dimer to fibril t ransition.