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Understanding the precise contribution of <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1\u2010 and <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2\u2010dependent \u03b3\u2010secretases to the production of \u03b2\u2010amyloid peptide (A\u03b2) from amyloid precursor protein (<jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content>) remains an important challenge to design molecules efficiently modulating A\u03b2 release without affecting the processing of other \u03b3\u2010secretase substrates. To that end, we studied <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1\u2010 and <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2\u2010dependent substrate processing in murine cells lacking presenilins (<jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>s) (<jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> PS<\/jats:styled-content>2<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> or <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1\u2010<jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2 double\u2010<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> noted <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>d<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>) or stably re\u2010expressing human <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1 or <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2 in an endogenous <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>\u2010null (<jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>d<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>) background. We characterized the processing of <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content> and Notch on both endogenous and exogenous substrates, and we investigated the effect of pharmacological inhibitors targeting the <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>s activity (<jats:styled-content style=\"fixed-case\">DAPT<\/jats:styled-content> and L\u2010685,458). We found that murine <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1 \u03b3\u2010secretase plays a predominant role in <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content> and Notch processing when compared to murine <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2 \u03b3\u2010secretase. The inhibitors blocked more efficiently murine <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2\u2010 than murine <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1\u2010dependent processing. Human <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>s, especially human <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1, expression in a <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>\u2010null background efficiently restored <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content> and Notch processing. Strikingly, and contrary to the results obtained on murine <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>s, pharmacological inhibitors appear to preferentially target human <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1\u2010 than human <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>2\u2010dependent \u03b3\u2010secretase activity.<\/jats:p>","DOI":"10.1111\/jcmm.13364","type":"journal-article","created":{"date-parts":[[2017,10,10]],"date-time":"2017-10-10T06:52:41Z","timestamp":1507618361000},"page":"823-833","source":"Crossref","is-referenced-by-count":31,"title":["Specificity of presenilin\u20101\u2010 and presenilin\u20102\u2010dependent \u03b3\u2010secretases towards substrate processing"],"prefix":"10.1111","volume":"22","author":[{"given":"Serena","family":"Stanga","sequence":"first","affiliation":[{"name":"Alzheimer Research group Institute of Neuroscience Universit\u00e9 catholique de Louvain Brussels 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