{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:24:27Z","timestamp":1777861467857,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515110836"],"award-info":[{"award-number":["2023A1515110836"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013314","name":"111 Project","doi-asserted-by":"crossref","award":["B16009"],"award-info":[{"award-number":["B16009"]}],"id":[{"id":"10.13039\/501100013314","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Construction Project of Liaoning Provincial Key Laboratory, China","award":["2022JH13\/10200026"],"award-info":[{"award-number":["2022JH13\/10200026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The proteolytic processing of the amyloid precursor protein (APP) is a core pathological event in Alzheimer\u2019s disease (AD) pathogenesis, yet the global genetic regulatory networks modulating this process have not been fully characterized. To systematically identify novel regulators of APP cleavage, we performed a genome-wide CRISPR\/Cas9 knockout screen utilizing an optimized UAS-GAL4-based cellular reporter, and identified genetic modulators governing amyloidogenic and non-amyloidogenic processing. The screen uncovered distinct functional gene clusters regulating the APP, prominently involving cellular metabolism, protein modification, and vesicular trafficking. Specifically, LDHB, PIAS2, CCDC53, and TRIM61 emerged as novel functional modulators. Biochemical validation confirmed that ablating these genes significantly alters the metabolic balance between sAPP\u03b1 and amyloid-\u03b2 (A\u03b2) production. Finally, integration with human AD transcriptomic datasets demonstrated that these identified modulators undergo significant dysregulation in clinics. Together, these findings establish a reporter-based functional screening framework for APP processing and identify candidate regulatory nodes linked to metabolism, protein modification, and vesicular trafficking. These candidates provide a resource for future mechanistic investigation and validation in more disease-relevant AD models.<\/jats:p>","DOI":"10.3390\/ijms27093926","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:26:41Z","timestamp":1777382801000},"page":"3926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-Wide CRISPR Screening Identifies Genetic Modulators of Amyloid Precursor Protein Processing"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-0730","authenticated-orcid":false,"given":"You","family":"Li","sequence":"first","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjia","family":"Yao","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9156-9778","authenticated-orcid":false,"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Northeastern University, Shenyang 110819, China"},{"name":"Key Laboratory of Data Analytics and Optimization for Smart Industry (Northeastern University), Ministry of Education, Shenyang 110819, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiling","family":"Gao","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-0450","authenticated-orcid":false,"given":"Teng","family":"Fei","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Brain-Computer Interface, Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China"},{"name":"Foshan Graduate School of Innovation, Northeastern University, Foshan 528311, China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems 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