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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,13]]},"abstract":"<jats:p>The formation of toxic Amyloid \u03b2-peptide (A\u03b2) oligomers is one of the earliest events in the molecular pathology of Alzheimer\u2019s Disease (AD). These oligomers lead to a variety of downstream effects, including impaired neuronal signaling, neuroinflammation, tau phosphorylation, and neurodegeneration, and it is estimated that these events begin 10 to 20 y before the presentation of symptoms. Toxic A\u03b2 oligomers contain a nonstandard protein structure, termed \u03b1-sheet, and designed \u03b1\u2013sheet peptides target this main-chain structure in toxic oligomers independent of sequence. Here we show that a designed \u03b1\u2013sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic \u03b1\u2013sheet-containing A\u03b2 oligomers produce strong SOBA signals, while monomeric and \u03b2-sheet protofibrillar A\u03b2 do not. \u03b1\u2013sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, we developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected A\u03b2 oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, we adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson\u2019s disease and Lewy body dementia.<\/jats:p>","DOI":"10.1073\/pnas.2213157119","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T13:50:42Z","timestamp":1670593842000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers"],"prefix":"10.1073","volume":"119","author":[{"given":"Dylan","family":"Shea","sequence":"first","affiliation":[{"name":"Molecular Engineering Program, University of Washington, Seattle, WA 98105"},{"name":"Department of Bioengineering, University of Washington, Seattle, WA 98105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3259-0098","authenticated-orcid":false,"given":"Elizabeth","family":"Colasurdo","sequence":"additional","affiliation":[{"name":"Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, WA 98108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0001-8484","authenticated-orcid":false,"given":"Alec","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Washington, Seattle, 98105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-9408","authenticated-orcid":false,"given":"Courtnie","family":"Paschall","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, WA 98105"},{"name":"Department of Neurosurgery, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Jayadev","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5291-1469","authenticated-orcid":false,"given":"C. Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Galasko","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-9891","authenticated-orcid":false,"given":"Andrew","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7780-2042","authenticated-orcid":false,"given":"Ge","family":"Li","sequence":"additional","affiliation":[{"name":"Mental Illness Research, Education and Clinical Center Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108"},{"name":"Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108"},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Peskind","sequence":"additional","affiliation":[{"name":"Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, Seattle, WA 98108"},{"name":"Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Daggett","sequence":"additional","affiliation":[{"name":"Molecular Engineering Program, University of Washington, Seattle, WA 98105"},{"name":"Department of Bioengineering, University of Washington, Seattle, WA 98105"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"e_1_3_5_1_2","unstructured":"Alzheimer\u2019s Association Alzheimer\u2019s disease facts and figures.https:\/\/www.alz.org\/media\/Documents\/alzheimers-facts-and-figures.pdf https:\/\/www.alz.org\/alzheimers-dementia\/facts-figures (2022). 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