Transthyretin-derived peptides as ?-amyloid inhibitors.

ABSTRACT: Self-association of ?-amyloid (A?) into soluble oligomers and fibrillar aggregates is associated with Alzheimer's disease pathology, motivating the search for compounds that selectively bind to and inhibit A? oligomerization and/or neurotoxicity. Numerous small-molecule inhibitors of A? aggregation or toxicity have been reported in the literature. However, because of their greater size and complexity, peptides and peptidomimetics may afford improved specificity and affinity as A? aggregation modulators compared to small molecules. Two divergent strategies have been employed in the search for peptides that bind A?: (i) using recognition domains corresponding to sequences in A? itself (such as KLVFF) and (ii) screening random peptide-based libraries. In this study, we propose a third strategy, specifically, designing peptides that mimic binding domains of A?-binding proteins. Transthyretin, a plasma transport protein that is also relatively abundant in cerebrospinal fluid, has been shown to bind to A?, inhibit aggregation, and reduce its toxicity. Previously, we identified strand G of transthyretin as a specific A? binding domain. In this work we further explore and define the necessary features of this binding domain. We demonstrate that peptides derived from transthyretin bind A? and inhibit its toxicity. We also show that, although both transthyretin and transthyretin-derived peptides bind A? and inhibit toxicity, they differ significantly in their effect on A? aggregation.

SUBMITTER: Cho PY 

PROVIDER: S-EPMC4102968 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature