{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T10:14:14Z","timestamp":1768817654496,"version":"3.49.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Neuroinflammation driven by microglial activation represents a pivotal pathological mechanism underlying brain injury in Alzheimer's disease (AD), with NLRP3 inflammasome activation being a hallmark feature of this process. Netrin-1 (NTN-1) was recently shown to have potent anti-inflammatory and anti-apoptotic properties in a range of inflammatory diseases; however, its potential effect on neuroinflammation in AD treatment has not been well examined. Accordingly, this study aimed to investigate the effects of NTN-1 on cognitive impairment and to explore the anti-inflammatory properties related to the NLRP3 inflammasome and NF-\u03baB signaling in A\u03b21-42-induced rat models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed the effects of NTN-1 on neurobehavioral function, microglial activation and neuroinflammation mechanisms in A\u03b21-42-treated rats using the Morris water maze test and Western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results indicated that microinjections of NTN-1 attenuated A\u03b21-42-induced memory and cognitive dysfunction and significantly inhibited microglial proliferation and NLRP3 inflammasome activation in the hippocampus and cortex of AD rats. Additionally, NTN-1 effectively prevented proinflammatory factor (IL1\u03b2 and IL18) release and NF-\u03baB signaling upstream activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Overall, the results of the present study indicated that exogenous NTN-1 treatment prevented neuroinflammation and cognitive deficits by inhibiting microglial activation, which is possibly mediated by the NF-\u03baB signaling pathway and NLRP3 inflammasome activation in A\u03b21-42-simulated rat models. NTN-1 emerges as a promising therapeutic candidate for mitigating microglia-mediated neuropathology in AD through its anti-inflammatory properties.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2025.1516399","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:31:35Z","timestamp":1745818295000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["NTN-1 attenuates amyloid-\u03b2-mediated microglial neuroinflammation and memory impairment via the NF-\u03baB pathway and NLRP3 inflammasome in a rat model of Alzheimer's disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Tianhang","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Chi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3989","DOI":"10.1523\/JNEUROSCI.1997-12.2013","article-title":"MicroRNA-195 protects against dementia induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats","volume":"33","author":"Ai","year":"2013","journal-title":"J. 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