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We previously reported that PS1 L271V increased amyloid beta (A\u03b2) 42\/40 ratios, while PS1<jats:sup>\u2206exon8<\/jats:sup>reduced A\u03b242\/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1<jats:sup>\u2206exon8<\/jats:sup>did not rescue A\u03b2 generation in PS1\/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1<jats:sup>\u2206exon8<\/jats:sup>is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1<jats:sup>\u2206exon8<\/jats:sup><jats:italic>in vivo<\/jats:italic>by crossing PS1<jats:sup>\u2206exon8<\/jats:sup>transgenics with either PS1-null or Dutch APP<jats:sup>E693Q<\/jats:sup>mice. As a control, we crossed APP<jats:sup>E693Q<\/jats:sup>with mice expressing a deletion in an adjacent exon (PS1<jats:sup>\u2206exon9<\/jats:sup>). PS1<jats:sup>\u2206exon8<\/jats:sup>did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function<jats:italic>in vivo<\/jats:italic>. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)\/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1<jats:sup>\u2206exon8<\/jats:sup>interacts with nicastrin, participating in the \u03b3\u2013secretase complex formation. These data support that catalytically inactive PS1<jats:sup>\u2206exon8<\/jats:sup>is generated physiologically and participates in protein-protein interactions.<\/jats:p>","DOI":"10.1038\/srep17042","type":"journal-article","created":{"date-parts":[[2015,11,26]],"date-time":"2015-11-26T10:16:04Z","timestamp":1448532964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1\u2212\/\u2212 phenotype and forms complexes with wildtype PS1 and nicastrin"],"prefix":"10.1038","volume":"5","author":[{"given":"Hannah","family":"Brautigam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar L.","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Bogush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dara L.","family":"Dickstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.J.","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter R.","family":"Schofield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopal","family":"Thinakaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Mathews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick R.","family":"Hof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Gandy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle E.","family":"Ehrlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,26]]},"reference":[{"key":"BFsrep17042_CR1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/sj.embor.7400897","volume":"8","author":"B De Strooper","year":"2007","unstructured":"De Strooper, B. 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