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Additionally, NEP\/IDE double knock-out further exacerbated the plaque deposition of\n<jats:italic>App<\/jats:italic>\n<jats:italic>\n<jats:sup>NL-F<\/jats:sup>\n<\/jats:italic>\nmice, demonstrating a synergistic effect between the two enzymes. We also revealed that the M8V mutation in NEP reduced extracellular A\u03b2 degradation in SH-SY5Y neuroblastoma cells, not by impairing catalytic activity but by increasing phosphorylation at an intracellular serine residue. This alteration in phosphorylation decreases NEP localization on the cell surface and extracellular vesicles, thereby limiting extracellular A\u03b2 degradation. These observations point to the role of aging-associated neprilysin decline in sporadic AD pathogenesis and endorse the strategy of upregulating neprilysin activity to treat preclinical AD.\n<\/jats:p>","DOI":"10.1523\/jneurosci.2152-24.2025","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T17:55:30Z","timestamp":1745949330000},"page":"e2152242025","source":"Crossref","is-referenced-by-count":19,"title":["The Role of Neprilysin and Insulin-Degrading Enzyme in the Etiology of Sporadic Alzheimer's Disease"],"prefix":"10.1523","volume":"45","author":[{"given":"Takahiro","family":"Morito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Takamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Watamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomasa","family":"Kakiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Fujioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Mihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misaki","family":"Sekiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Watanabe-Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Kamano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Matsuba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tsubuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-7947","authenticated-orcid":false,"given":"Nobuhisa","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Sasaguri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"2025060411001473000_45.23.e2152242025.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(01)02390-3"},{"key":"2025060411001473000_45.23.e2152242025.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.01.020"},{"key":"2025060411001473000_45.23.e2152242025.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202753"},{"key":"2025060411001473000_45.23.e2152242025.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.04.060"},{"key":"2025060411001473000_45.23.e2152242025.5","doi-asserted-by":"crossref","unstructured":"Bellenguez C , et al. 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