{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T10:11:54Z","timestamp":1778580714404,"version":"3.51.4"},"reference-count":80,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,9,26]],"date-time":"2018-09-26T00:00:00Z","timestamp":1537920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["1120\/3\u20101; RTG1331"],"award-info":[{"award-number":["1120\/3\u20101; RTG1331"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2018,10]]},"abstract":"Abstract<\/jats:title>The initial step in the amyloidogenic cascade of amyloid precursor protein (APP<\/jats:styled-content>) processing is catalyzed by beta\u2010site APP<\/jats:styled-content>\u2010cleaving enzyme (BACE<\/jats:styled-content>), and this protease has increased activities in affected areas of Alzheimer's disease brains. We hypothesized that altered APP<\/jats:styled-content> processing, because of augmented BACE<\/jats:styled-content> activity, would affect the actions of direct and indirect BACE<\/jats:styled-content> inhibitors. We therefore compared post\u2010mitotic human neurons (LUHMES<\/jats:styled-content>) with their BACE<\/jats:styled-content>\u2010overexpressing counterparts (B<\/jats:styled-content>LUHMES<\/jats:styled-content>). Although \u03b2\u2010cleavage of APP<\/jats:styled-content> was strongly increased in BLUHMES<\/jats:styled-content>, they produced less full\u2010length and truncated amyloid beta (A\u03b2) than LUHMES<\/jats:styled-content>. Moreover, low concentrations of BACE<\/jats:styled-content> inhibitors decreased cellular BACE<\/jats:styled-content> activity as expected, but increased A\u03b21\u201040<\/jats:sub> levels. Several other approaches to modulate BACE<\/jats:styled-content> activity led to a similar, apparently paradoxical, behavior. For instance, reduction in intracellular acidification by bepridil increased A\u03b2 production in parallel with decreased BACE<\/jats:styled-content> activity. In contrast to BLUHMES<\/jats:styled-content>, the respective control cells (LUHMES<\/jats:styled-content> or BLUHMES<\/jats:styled-content> with catalytically inactive BACE<\/jats:styled-content>) showed conventional pharmacological responses. Other non\u2010canonical neurochemical responses (so\u2010called \u2018rebound effects\u2019) are well\u2010documented for the A\u03b2 pathway, especially for \u03b3\u2010secretase: a partial block of its activity leads to an increased A\u03b2 secretion by some cell types. We therefore compared LUHMES<\/jats:styled-content> and BLUHMES<\/jats:styled-content> regarding rebound effects of \u03b3\u2010secretase inhibitors and found an A\u03b2 rise in LUHMES<\/jats:styled-content> but not in BLUHMES<\/jats:styled-content>. Thus, different cellular factors are responsible for the \u03b3\u2010secretase\u2010 versus BACE<\/jats:styled-content>\u2010related A\u03b2 rebound. We conclude that increased BACE<\/jats:styled-content> activity, possibly accompanied by an altered cellular localization pattern, can dramatically influence A\u03b2 generation in human neurons and affect pharmacological responses to secretase inhibitors.<\/jats:p><\/jats:sec>Open Practices<\/jats:title><\/jats:p>Open Science: This manuscript was awarded with the Open Materials Badge.<\/jats:p>For more information see: https:\/\/cos.io\/our-services\/open-science-badges\/<\/jats:ext-link><\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14467","type":"journal-article","created":{"date-parts":[[2018,5,27]],"date-time":"2018-05-27T08:09:15Z","timestamp":1527408555000},"page":"256-274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Reduced A\u03b2 secretion by human neurons under\u00a0conditions of strongly increased BACE<\/scp> activity"],"prefix":"10.1111","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9869-7296","authenticated-orcid":false,"given":"Diana","family":"Scholz","sequence":"first","affiliation":[{"name":"Chair for in\u00a0vitro Toxicology and Biomedicine University of Konstanz Konstanz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yana","family":"Chernyshova","sequence":"additional","affiliation":[{"name":"Chair for in\u00a0vitro Toxicology and Biomedicine University of Konstanz Konstanz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna\u2010Katharina","family":"\u00dcckert","sequence":"additional","affiliation":[{"name":"Chair for in\u00a0vitro Toxicology and Biomedicine University of Konstanz Konstanz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3778-8693","authenticated-orcid":false,"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[{"name":"Chair for in\u00a0vitro Toxicology and Biomedicine University of Konstanz Konstanz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,9,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.08.130"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-11-04421.1999"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414248200"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0705408"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M009899200"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005339200"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-3042.2002.00770.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804175200"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/85064"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.01.011"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003202200"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409680200"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409272200"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-100109-104117"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2009.218"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2013.59"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205012666141218125042"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.2174\/156720508783954695"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0312-8"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211485200"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.59.9.1381"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12937"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja000300g"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1998.71051920.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600061"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/357500a0"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a003040"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002095200"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0106-11"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-106666"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004175200"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111141200"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0751085.x"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.01.064"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200201123"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1159\/000095267"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2015.97"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.5.3173"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32449-3"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.109.5.991"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3872-10.2010"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.106.110700"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1385\/MB:29:1:47"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210105200"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200301115"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200407070"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07560.x"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi015800g"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1746-05.2005"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/85059"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031084"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1508"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1199-10.2010"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)90269-Q"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-017-1966-1"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2004-6107"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04543"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.27.18851"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22308"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2513-11.2011"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507016200"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2009.07.027"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12226"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07255.x"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.03.012"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(96)00002-9"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm049379g"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr034"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800019200"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1743"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5440.735"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3657-09.2009"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.09.028"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2009.01.008"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011116200"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90177-3"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07501.x"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104350200"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0103-3"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0997-871"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.14467","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.14467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:15:43Z","timestamp":1694736943000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.14467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,26]]},"references-count":80,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1111\/jnc.14467"],"URL":"https:\/\/doi.org\/10.1111\/jnc.14467","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,26]]},"assertion":[{"value":"2018-01-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}