The neuronal S100B protein is a calcium-tuned suppressor of amyloid-? aggregation.

ABSTRACT: Amyloid-? (A?) aggregation and neuroinflammation are consistent features in Alzheimer's disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized biomarker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of A?42 aggregation and toxicity. We determined the structural details of the interaction between monomeric A?42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered A?42 into an ?-helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of A?42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of A?42 aggregation by interacting with A?42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface-catalyzed reactions through S100B binding to growing A?42 oligomers and fibrils. S100B protects cells from A?42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by A?42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration.

SUBMITTER: Cristovao JS 

PROVIDER: S-EPMC6025902 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature