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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>\n                    Transient soluble oligomers of amyloid-\u03b2 (A\u03b2) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer\u2019s disease (AD). Synthetic cyclic D,L-\u03b1-peptides (e.g.,\n                    <jats:bold>1<\/jats:bold>\n                    ) self-assemble into cross \u03b2-sheet nanotubes, react with early A\u03b2 species (1-3 mers), and inhibit A\u03b2 aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly\n                    <jats:sup>6<\/jats:sup>\n                    ]-\n                    <jats:bold>1<\/jats:bold>\n                    inhibited A\u03b2 aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly\n                    <jats:sup>6<\/jats:sup>\n                    ]-\n                    <jats:bold>1<\/jats:bold>\n                    and A\u03b242 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable\n                    <jats:sup>64<\/jats:sup>\n                    Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where A\u03b2 oligomers may spread to other brain parts with disease progression. Compared with standard\n                    <jats:sup>11<\/jats:sup>\n                    C-labeled Pittsburgh compound-B (\n                    <jats:sup>11<\/jats:sup>\n                    C-PIB), which binds specifically fibrillar A\u03b2 plaques,\n                    <jats:sup>64<\/jats:sup>\n                    Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with A\u03b2 oligomer levels. Effectively crossing the blood\u2013brain barrier (BBB), peptide\n                    <jats:bold>1<\/jats:bold>\n                    and [azaGly\n                    <jats:sup>6<\/jats:sup>\n                    ]-\n                    <jats:bold>1<\/jats:bold>\n                    reduced A\u03b2 oligomer levels, prolonged lifespan of AD transgenic\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2210766119","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T17:14:31Z","timestamp":1669655671000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":81,"title":["Early diagnosis and treatment of Alzheimer\u2019s disease by targeting toxic soluble A\u03b2 oligomers"],"prefix":"10.1073","volume":"119","author":[{"given":"Maram","family":"Habashi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Vutla","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Chimie, Universit\u00e9 de Montr\u00e9al, Complexe des Sciences, Qu\u00e9bec H2V 0B3, 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