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Neurosci."],"abstract":"<jats:p>Extracellular aggregation of the amyloid-\u03b2 1\u201342 (A\u03b242) peptide is a major hallmark of Alzheimer\u2019s disease (AD), with recent data suggesting that A\u03b2 intermediate oligomers (A\u03b2O) are more cytotoxic than mature amyloid fibrils. Understanding how chaperones harness such amyloid oligomers is critical toward establishing the mechanisms underlying regulation of proteostasis in the diseased brain. This includes S100B, an extracellular signaling Ca<jats:sup>2+<\/jats:sup>-binding protein which is increased in AD as a response to neuronal damage and whose holdase-type chaperone activity was recently unveiled. Driven by this evidence, we here investigate how different S100B chaperone multimers influence the formation of oligomers during A\u03b242 fibrillation. Resorting to kinetic analysis coupled with simulation of A\u03b2O influx distributions, we establish that supra-stoichiometric ratios of dimeric S100B-Ca<jats:sup>2+<\/jats:sup> drastically decrease A\u03b242 oligomerization rate by 95% and A\u03b2O levels by 70% due to preferential inhibition of surface-catalyzed secondary nucleation, with a concomitant redirection of aggregation toward elongation. We also determined that sub-molar ratios of tetrameric apo-S100B decrease A\u03b242 oligomerization influx down to 10%, while precluding both secondary nucleation and, more discreetly, fibril elongation. Coincidently, the mechanistic predictions comply with the independent screening of A\u03b2O using a combination of the thioflavin-T and X-34 fluorophores. Altogether, our findings illustrate that different S100B multimers act as complementary suppressors of A\u03b242 oligomerization and aggregation, further underpinning their potential neuroprotective role in AD.<\/jats:p>","DOI":"10.3389\/fnins.2023.1162741","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T04:34:33Z","timestamp":1679373273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["S100B chaperone multimers suppress the formation of oligomers during A\u03b242 aggregation"],"prefix":"10.3389","volume":"17","author":[{"given":"Ant\u00f3nio J.","family":"Figueira","sequence":"first","affiliation":[]},{"given":"Joana","family":"Saavedra","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Cardoso","sequence":"additional","affiliation":[]},{"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13509","DOI":"10.1073\/pnas.1919464117","article-title":"Rational design of a conformation-specific antibody for the quantification of A\u03b2 oligomers.","volume":"117","author":"Aprile Francesco","year":"2020","journal-title":"Proc. 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