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The S100B Alarmin Is a Dual-Function Chaperone Suppressing Amyloid‑β Oligomerization through Combined Zinc Chelation and Inhibition of Protein Aggregation
journal contribution
posted on 2020-08-07, 13:34 authored by Joana
S. Cristóvão, António
J. Figueira, Ana P. Carapeto, Mário S. Rodrigues, Isabel Cardoso, Cláudio M. GomesAmyloid beta (Aβ)
aggregation and imbalance of metal ions
are major hallmarks of Alzheimer’s disease (AD). Indeed, amyloid
plaques of AD patients are enriched in zinc and Aβ42, and AD
related-cognitive decline is dependent on extracellular zinc concentration. In vitro, zinc induces the formation of polymorphic Aβ42
oligomers that delay the formation of amyloid fibers at the expense
of increased cellular toxicity. S100B is an inflammatory alarmin and
one of the most abundant proteins in the brain and is upregulated
in AD and associated with amyloid plaques, where it exerts extracellular
functions. Recent findings have uncovered novel neuroprotective functions
for S100B as a suppressor of Aβ aggregation and toxicity and
in the regulation of zinc homeostasis in neurons. Here we combine
biophysical and kinetic approaches to demonstrate that such S100B
protective functions converge, making the protein a dual-function
chaperone capable of suppressing the formation of toxic Aβ oligomers
through both chelation of zinc and inhibition of protein aggregation.
From detailed kinetic analysis of Aβ42 aggregation monitoring
ThT fluorescence, we show that substoichiometric S100B prevents the
formation of toxic off-pathway oligomers that are formed by monomeric
Aβ42 in the presence of zinc. Indeed, S100B is effective when
added during the lag and transition phases of Aβ42 aggregation,
and its action under these circumstances results from its ability
to buffer zinc, as it perfectly mimics the effect obtained with the
chelating agent EDTA. Further, bioimaging analysis combining transmission
electron microscopy and atomic force microscopy confirms that catalytic
amounts of S100B partly revert the formation of toxic oligomers. Taken
together these results indicate a new role for S100B as a dual chaperone
whose distinct functions are interrelated and depend on the relative
levels of zinc, S100B, and Aβ, which dynamically evolve during
AD.