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However, whether targeting intracellular A\u03b2 can halt disease progression and how this can be achieved in vivo remain unknown. While investigating the brain transcriptional responses to A\u03b2 pathology, we identify a neuroprotective role for the serine protease Yip7 in a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    AD model. Neuronal overexpression of\n                    <jats:italic>yip7<\/jats:italic>\n                    alleviates multiple A\u03b242\u2010induced deficits, including declines in locomotor activity, impaired proteostasis, increased brain aging and neuronal death, and shortened lifespan. Unlike canonical digestive proteases, Yip7 is not secreted but instead localized to the endosomal\/lysosomal compartments via a putative transmembrane domain initially predicted as a signal peptide. Crucially, Yip7's neuroprotective function depends on its proper subcellular localization rather than the catalytic triad. Mechanistically, rather than eliminating A\u03b2, Yip7 binds intracellular A\u03b242 to increase its neuronal retention, and this unexpectedly reduces A\u03b242 toxicity to the organism. Finally, transcriptomics reveals that protection against A\u03b242 toxicity by Yip7 is associated with selective suppression of A\u03b2\u2010upregulated genes including those codingribosomal proteins and molecular chaperones for protein folding. Together, these findings introduce a novel concept that intracellular sequestration of A\u03b2 can be explored to mitigate its neurotoxicity.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517862","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T19:17:33Z","timestamp":1773861453000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intracellular A\u03b242 Sequestration by a Serine Protease Mitigates Neurotoxicity in a\n                    <i>Drosophila<\/i>\n                    Alzheimer's Disease Model"],"prefix":"10.1002","volume":"13","author":[{"given":"Jingyun","family":"Su","sequence":"first","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation College of Life Sciences Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation College of Life Sciences Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation College of Life Sciences Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pa","family":"Wu","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation College of Life Sciences Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3987-7742","authenticated-orcid":false,"given":"Zongzhao","family":"Zhai","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation College of Life Sciences Hunan Normal University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001911\u20103"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1566067"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001484\u20107"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010023\u201000637\u20100"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44319\u2010024\u201000294\u20104"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010021\u201001249\u20100"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2168"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.09.001"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010022\u201001024\u2010z"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100311\u20109"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2017.08.003"},{"key":"e_1_2_9_13_1","first-page":"8","article-title":"Intracellular Accumulation of Amyloid\u2010Beta\u2014A Predictor for Synaptic Dysfunction and Neuron Loss in Alzheimer's Disease","volume":"2","author":"Bayer T. 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