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However, intermediate soluble oligomers of A\u03b2 are now recognized as initiators of the pathogenic cascade leading to AD. Studies using recombinant A\u03b2 have shown that hexameric A\u03b2 in particular acts as a critical nucleus for A\u03b2 self-assembly. We recently isolated hexameric A\u03b2 assemblies from a cellular model, and demonstrated their ability to enhance A\u03b2 aggregation in vitro. Here, we report the presence of similar hexameric-like A\u03b2 assemblies across several cellular models, including neuronal-like cell lines. In order to better understand how they are produced in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in their formation. PS1 and PS2 are the catalytic subunits of the \u03b3-secretase complex that generates A\u03b2. Using CRISPR-Cas9 to\n                    <jats:italic>knockdown<\/jats:italic>\n                    each of the two presenilins in neuronal-like cell lines, we observed a direct link between the PS2-dependent processing pathway and the release of hexameric-like A\u03b2 assemblies in extracellular vesicles. Further, we assessed the contribution of hexameric A\u03b2 to the development of amyloid pathology. We report the early presence of hexameric-like A\u03b2 assemblies in both transgenic mice brains exhibiting human A\u03b2 pathology and in the cerebrospinal fluid of AD patients, suggesting hexameric A\u03b2 as a potential early AD biomarker. Finally, cell-derived hexameric A\u03b2 was found to seed other human A\u03b2 forms, resulting in the aggravation of amyloid deposition in vivo and neuronal toxicity in vitro.\n                  <\/jats:p>","DOI":"10.1007\/s12035-021-02567-8","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T06:56:49Z","timestamp":1633417009000},"page":"6647-6669","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric \u03b2-Amyloid Assemblies"],"prefix":"10.1007","volume":"58","author":[{"given":"C\u00e9line","family":"Vrancx","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devkee M.","family":"Vadukul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Suelves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Contino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"D\u2019Auria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"van Pesch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Hanseeuw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lo\u00efc","family":"Quinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1086-2942","authenticated-orcid":false,"given":"Pascal","family":"Kienlen-Campard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"issue":"5","key":"2567_CR1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006270","volume":"2","author":"C Haass","year":"2012","unstructured":"Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. 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