{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:17:10Z","timestamp":1791328630402,"version":"4.3.1"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"35","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,8,31]]},"abstract":"<jats:p>\n                    Soluble oligomeric aggregates of the amyloid-\u03b2 peptide (A\u03b2) have been implicated in the pathogenesis of Alzheimer\u2019s disease (AD). Although the conformation adopted by A\u03b2 within these aggregates is not known, a \u03b2-hairpin conformation is known to be accessible to monomeric A\u03b2. Here we show that this \u03b2-hairpin is a building block of toxic A\u03b2 oligomers by engineering a double-cysteine mutant (called A\u03b2\n                    <jats:sc>cc<\/jats:sc>\n                    ) in which the \u03b2-hairpin is stabilized by an intramolecular disulfide bond. A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    <jats:sc>cc<\/jats:sc>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    <jats:sc>cc<\/jats:sc>\n                    both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect A\u03b2 aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in A\u03b2\n                    <jats:sc>cc<\/jats:sc>\n                    oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that \u03b2-sheet-containing A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    <jats:sc>cc<\/jats:sc>\n                    oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    , in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic A\u03b2 oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    is more toxic than the shorter A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    , and why certain inherited mutations are linked to protofibril formation and early-onset AD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1001740107","type":"journal-article","created":{"date-parts":[[2010,8,17]],"date-time":"2010-08-17T00:40:39Z","timestamp":1282005639000},"page":"15595-15600","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":340,"title":["Stabilization of neurotoxic Alzheimer amyloid-\u03b2 oligomers by protein engineering"],"prefix":"10.1073","volume":"107","author":[{"given":"Anders","family":"Sandberg","sequence":"first","affiliation":[{"name":"Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila M.","family":"Luheshi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"S\u00f6llvander","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences\/Geriatrics, Uppsala University, SE-751 25 Uppsala, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Pereira de Barros","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertil","family":"Macao","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas P. J.","family":"Knowles","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Biverst\u00e5l","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Swedish University of Agricultural Sciences (SLU), Uppsala Biomedical Center, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christofer","family":"Lendel","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Swedish University of Agricultural Sciences (SLU), Uppsala Biomedical Center, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frida","family":"Ekholm-Petterson","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences\/Geriatrics, Uppsala University, SE-751 25 Uppsala, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoly","family":"Dubnovitsky","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Swedish University of Agricultural Sciences (SLU), Uppsala Biomedical Center, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Lannfelt","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences\/Geriatrics, Uppsala University, SE-751 25 Uppsala, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dobson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torleif","family":"H\u00e4rd","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Swedish University of Agricultural Sciences (SLU), Uppsala Biomedical Center, SE-751 24 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,8,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.101304.123901"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800036200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1782"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04533"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607483200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.6448"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.01.010"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1189-06.2006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.3559"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.26.010302.081142"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn0901-887"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.07.003"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03680"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja036813f"},{"key":"e_1_3_3_15_2","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1002\/prot.22775","article-title":"Comparing the folding free-energy landscape of A\u03b242 variants with different aggregation properties","volume":"78","author":"Mitternacht S","year":"2010","unstructured":"S Mitternacht, I Staneva, T H\u00e4rd, A Irb\u00e4ck, Comparing the folding free-energy landscape of A\u03b242 variants with different aggregation properties. 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