{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:19:34Z","timestamp":1788009574724,"version":"build-2784847793"},"reference-count":96,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Insulin-degrading enzyme (IDE) plays a critical role in regulating insulin levels in various tissues, including the brain, liver, and kidneys. In type 2 diabetes mellitus (T2DM), key features include insulin resistance, elevated insulin levels in the blood, and hyperglycemia. In this context, the function of IDE becomes particularly important; however, in T2DM, IDE\u2019s function can be impaired. Notably, individuals with T2DM have a higher risk of developing Alzheimer\u2019s disease (AD), suggesting that impaired IDE function may contribute to both diabetes and neurodegeneration. IDE has been studied for its ability to degrade Amyloid-\u03b2 peptides, the primary constituents of amyloid plaques in AD. However, its role in A\u03b2 clearance in vivo remains debated due to limited enzymatic efficacy under physiological conditions and differences in subcellular localization between IDE and its putative substrate. Other proteases, such as neprilysin, appear to play a more prominent role in preventing plaque formation. Additionally, the long-standing hypothesis that insulin competes with A\u03b2 for IDE activity has been questioned, as brain insulin levels are too low to inhibit A\u03b2 degradation significantly. Genetic variants in the IDE gene have been associated with increased AD risk, although the mechanisms by which they alter enzyme function are not yet fully understood. A deeper understanding of IDE\u2019s role in the context of both metabolic and neurodegenerative diseases may provide valuable insights for the development of new therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26146693","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T10:55:41Z","timestamp":1752490541000},"page":"6693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Understanding the Insulin-Degrading Enzyme: A New Look at Alzheimer\u2019s Disease and A\u03b2 Plaque Management"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0198-8238","authenticated-orcid":false,"given":"Michele","family":"Cerasuolo","sequence":"first","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Auriemma","sequence":"additional","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Di Meo","sequence":"additional","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Lenti","sequence":"additional","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6609-7453","authenticated-orcid":false,"given":"Michele","family":"Papa","sequence":"additional","affiliation":[{"name":"Laboratory of Neuronal Networks Morphology and System Biology, Department Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-455X","authenticated-orcid":false,"given":"Giuseppe","family":"Paolisso","sequence":"additional","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Saint Camillus International University of Health and Medical Sciences (UniCamillus), 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1023-4260","authenticated-orcid":false,"given":"Maria Rosaria","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Advanced Clinical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., Ostolaza, H., and Mart\u00edn, C. 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