Design and Characterization of Chemically Stabilized A?42 Oligomers.

ABSTRACT: A popular working hypothesis of Alzheimer's disease causation is amyloid ?-protein oligomers are the key neuropathogenetic agents. Rigorously elucidating the role of oligomers requires the production of stable oligomers of each size. We previously used zero-length photochemical cross-linking to allow stabilization, isolation, and determination of structure-activity relationships of pure populations of A?40 dimers, trimers, and tetramers. We also attempted to study A?42 but found that A?42 oligomers subjected to the same procedures were not completely stable. On the basis of the fact that Tyr is a critical residue in cross-linking chemistry, we reasoned that the chemical accessibility of Tyr10 in A?42 must differ from that in A?40. We thus chemically synthesized four singly substituted Tyr variants that placed the Tyr in different positions across the A?42 sequence. We then studied the stability of the resulting cross-linked oligomers as well as procedures for fractionating the oligomers to obtain pure populations of different sizes. We found that [Phe(10),Tyr(42)]A?42 produced stable oligomers yielding highly pure populations of dimers through heptamers. This provides the means to establish formal structure-activity relationships of these important A?42 assemblies. In addition, we were able to analyze the dissociation patterns of non-cross-linked oligomers to produce a model for oligomer formation. This work is relevant to the determination of structure-activity relationships that have the potential to provide mechanistic insights into disease pathogenesis.

SUBMITTER: Yamin G 

PROVIDER: S-EPMC5104494 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature