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Generation of A\u03b2 from amyloid precursor protein (APP) by two enzymes, \u03b2- and \u03b3-secretase, has therefore been in the AD research spotlight for decades. Despite this, how the physical interaction of APP with the secretases influences APP processing is not fully understood. Herein, we compared two genetically identical human iPSC-derived neuronal cell types: low A\u03b2-secreting neuroprogenitor cells (NPCs) and high A\u03b2-secreting mature neurons, as models of low versus high A\u03b2 production. We investigated levels of substrate, enzymes and products of APP amyloidogenic processing and correlated them with the proximity of APP to \u03b2- and \u03b3-secretase in endo-lysosomal organelles. In mature neurons, increased colocalization of full-length APP with the \u03b2-secretase BACE1 correlated with increased \u03b2-cleavage product sAPP\u03b2. Increased flAPP\/BACE1 colocalization was mainly found in early endosomes. In the same way, increased colocalization of APP-derived C-terminal fragment (CTF) with presenilin-1 (PSEN1), the catalytic subunit of \u03b3-secretase, was seen in neurons as compared to NPCs. Furthermore, most of the interaction of APP with BACE1 in low A\u03b2-secreting NPCs seemed to derive from CTF, the remaining APP part after BACE1 cleavage, indicating a possible novel product-enzyme inhibition. In conclusion, our results suggest that interaction of APP and APP cleavage products with their secretases can regulate A\u03b2 production both positively and negatively. \u03b2- and \u03b3-Secretases are difficult targets for AD treatment due to their ubiquitous nature and wide range of substrates. Therefore, targeting APP-secretase interactions could be a novel treatment strategy for AD.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>\n                <jats:p>Colocalization of APP species with BACE1 in a novel model of low- versus high-A\u03b2 secretion\u2014Two genetically identical human iPSC-derived neuronal cell types: low A\u03b2-secreting neuroprogenitor cells (NPCs) and high A\u03b2 secreting mature neurons, were compared. Increased full-length APP (flAPP)\/BACE1 colocalization in early endosomes was seen in neurons, while APP-CTF\/BACE1 colocalization was much higher than flAPP\/BACE1 colocalization in NPCs, although the cellular location was not determined.<\/jats:p>","DOI":"10.1007\/s10571-023-01374-0","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T21:02:15Z","timestamp":1687640535000},"page":"3653-3668","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["APP-BACE1 Interaction and Intracellular Localization Regulate A\u03b2 Production in iPSC-Derived Cortical Neurons"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2998-3760","authenticated-orcid":false,"given":"Sandra","family":"Roselli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-1650","authenticated-orcid":false,"given":"Tugce Munise","family":"Satir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2325-6407","authenticated-orcid":false,"given":"Rafael","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-7330","authenticated-orcid":false,"given":"Stefanie","family":"Fruhw\u00fcrth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1803-165X","authenticated-orcid":false,"given":"Petra","family":"Bergstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3816-7474","authenticated-orcid":false,"given":"Lotta","family":"Agholme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"issue":"5","key":"1374_CR1","doi-asserted-by":"publisher","first-page":"3073","DOI":"10.1007\/s12035-022-02733-6","volume":"59","author":"J Aow","year":"2022","unstructured":"Aow J, Huang T-R, Thinakaran G, Koo EH (2022) Enhanced cleavage of APP by co-expressed Bace1 alters the distribution of APP and its fragments in neuronal and non-neuronal cells. 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