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Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer\u2019s disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic A\u03b2 production, the importance of other APP metabolites and \u03b3-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with G\u03b1s protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.<\/jats:p>","DOI":"10.7554\/elife.15645","type":"journal-article","created":{"date-parts":[[2016,5,19]],"date-time":"2016-05-19T18:26:53Z","timestamp":1463682413000},"source":"Crossref","is-referenced-by-count":34,"title":["Loss of presenilin function is associated with a selective gain of APP function"],"prefix":"10.7554","volume":"5","author":[{"given":"Carole","family":"Deyts","sequence":"first","affiliation":[{"name":"Departments of Neurobiology, The University of Chicago, Chicago, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Clutter","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology, The University of Chicago, Chicago, United 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