{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:42:32Z","timestamp":1790775752822,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1163862"],"award-info":[{"award-number":["APP1163862"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["2013384"],"award-info":[{"award-number":["2013384"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Traffic"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Alzheimer's disease is associated with increased levels of amyloid beta (A\u03b2) generated by sequential intracellular cleavage of amyloid precursor protein (APP) by membrane\u2010bound secretases. However, the spatial and temporal APP cleavage events along the trafficking pathways are poorly defined. Here, we use the Retention Using Selective Hooks (RUSH) to compare in real time the anterograde trafficking and temporal cleavage events of wild\u2010type APP (APPwt) with the pathogenic Swedish APP (APPswe) and the disease\u2010protective Icelandic APP (APPice). The analyses revealed differences in the trafficking profiles and processing between APPwt and the APP familial mutations. While APPwt was predominantly processed by the \u03b2\u2010secretase, BACE1, following Golgi transport to the early endosomes, the transit of APPswe through the Golgi was prolonged and associated with enhanced amyloidogenic APP processing and A\u03b2 secretion. A 20\u00b0C block in cargo exit from the Golgi confirmed \u03b2\u2010 and \u03b3\u2010secretase processing of APPswe in the Golgi. Inhibition of the \u03b2\u2010secretase, BACE1, restored APPswe anterograde trafficking profile to that of APPwt. APPice was transported rapidly through the Golgi to the early endosomes with low levels of A\u03b2 production. This study has revealed different intracellular locations for the preferential cleavage of APPwt and APPswe and A\u03b2 production, and the Golgi as the major processing site for APPswe, findings relevant to understand the molecular basis of Alzheimer's disease.<\/jats:p>","DOI":"10.1111\/tra.12932","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T03:27:56Z","timestamp":1711423676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Spatial\u2013Temporal Mapping Reveals the Golgi as the Major Processing Site for the Pathogenic Swedish\n                    <scp>APP<\/scp>\n                    Mutation: Familial\n                    <scp>APP<\/scp>\n                    Mutant Shifts the Major\n                    <scp>APP<\/scp>\n                    Processing Site"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6244-4932","authenticated-orcid":false,"given":"Jingqi","family":"Wang","sequence":"first","affiliation":[{"name":"The Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5336-6503","authenticated-orcid":false,"given":"Paul A.","family":"Gleeson","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7448-8403","authenticated-orcid":false,"given":"Lou","family":"Fourriere","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,3,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.63"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.09.001"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2018.11.013"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9MD00337A"},{"issue":"1","key":"e_1_2_10_8_1","first-page":"1","article-title":"Alzheimer's Disease","volume":"25","author":"Lane C. 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Insights Into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity","volume":"9","author":"Ludewig S.","year":"2016","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1120086"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8070748"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2020.02.003"},{"key":"e_1_2_10_54_1","unstructured":"W.Toh \u201cThe Intracellular Trafficking Pathways of \u03b2\u2010Secretase and the Amyloid Precursor Protein in Alzheimer's Disease\u201d (PhD thesis Biochemistry and Molecular Biology University of Melbourne 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