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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:p>Central to Alzheimer\u2019s disease pathology are prefibrillar oligomer assemblies of amyloid-\u03b2 (A\u03b2) peptide. A widely discussed hypothesis proposes that amyloid-\u03b2 oligomers insert into neuronal lipid membranes, disrupting their integrity and causing a loss of cellular homeostasis in Alzheimer\u2019s disease. This membrane disruption is believed to be a major source of A\u03b2-induced neurotoxicity. Cryo electron tomography (cryo-ET) has facilitated 3D nanoscale imaging of A\u03b2-membrane interactions under near-native conditions. Analyses of small extracellular vesicles (sEVs) reveals that A\u03b2 oligomers including annular and curvilinear extended oligomers (CLEOs) exhibit extensive binding to cell-derived lipid membranes, including insertion into and carpeting of the lipid bilayer. Notably, these oligomeric assemblies were also internalized and concentrated within the cell-derived exosomes and other small sEVs. Enrichment of A\u03b2 oligomers within the vesicles typically ranged between 5 to 20 times the external A\u03b2 levels depending on the vesicle size and curvature. In contrast, monomeric and fibrillar forms of A\u03b2 displayed minimal membrane interaction. Once internalized CLEOs appear to be trapped in an oligomeric form and do not readily go on to form fibrils. Studies with vesicles of brain lipid extract indicate the A\u03b2 internalization does not require the presence of a membrane protein. Our in vitro studies underscore the membrane-disruptive capacity of oligomeric A\u03b2 species and suggest a role of sEVs in concentrating toxic A\u03b2 oligomers and transporting oligomers across the brain interstitium.<\/jats:p>","DOI":"10.1073\/pnas.2610068123","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T16:17:56Z","timestamp":1784045876000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["3D nanoscale imaging of amyloid-\u03b2 oligomer interactions with extracellular vesicles by cryo-ET"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7411-1809","authenticated-orcid":false,"given":"Anum","family":"Khursheed","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Shang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/03d7sax13","id-type":"ROR","asserted-by":"publisher"}],"name":"Wuhan Institute for Neuroscience and Neuroengineering, College of Life Sciences, South-Central Minzu University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Szwedziak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Microscopy and Image Analysis, University of Zurich","place":["Zurich, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir A.","family":"Volkov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7533-2964","authenticated-orcid":false,"given":"John H.","family":"Viles","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026zzn846","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Molecular and Cellular Biology, Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"M. 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