Stereochemical specificity of Alzheimer's disease beta-peptide assembly

The formation and growth of insoluble amyloid deposits composed primarily o f the human beta-amyloid peptide (A beta) in brain is an essentially invari ant feature of Alzheimer's disease (AD) and is widely believed to contribut e to the progressive neurodegeneration of the disorder. To probe the specif icity of amyloid formation and growth, we synthesized and examined the self -assembly of D- and L-stereoisomers of A beta in vitro. While both enantiom ers formed insoluble aggregates at similar rates with amyloid-like fibrilla r morphology, deposition of soluble A beta peptide onto preexisting A beta aggregates was stereospecific. Although the L-peptide deposited readily ont o immobilized L-A beta aggregates with first-order kinetic dependence on so luble peptide concentration. essentially no association between the D-pepti de and L-template was observed. Similarly, the D-peptide deposited with fir st-order kinetics onto a D-A beta aggregate template but did not deposit on to a Similar template composed of aggregates of the L-enantiomer. Furthermo re, although the L-np isomer deposited onto authentic AD amyloid in prepara tions of unfixed AD brain, no focal association benz een the D-peptide and brain amyloid was detected These results establish that deposition of solub le A beta onto preexisting amyloid temperature is stereospecific, likely in volving direct docking interactions between peptide backbone and/or side ch ains rather than simple hydrophobic association. (C) 1998 John Wiley & Sons , Inc.