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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

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

Cristóvão Joana S JS Morris Vanessa K VK Cardoso Isabel I Leal Sónia S SS Martínez Javier J Botelho Hugo M HM Göbl Christoph C David Rodrigo R Kierdorf Katrin K Alemi Mobina M Madl Tobias T Fritz Günter G Reif Bernd B Gomes Cláudio M CM

Science advances 20180629 6

Amyloid-β (Aβ) 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 ...[more]

PMID: 29963623

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-? plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-? aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-? aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-? aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-? plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

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

Publications

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

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