{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:39:11Z","timestamp":1791916751562,"version":"4.3.4"},"reference-count":35,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T00:00:00Z","timestamp":1740873600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>As a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as a modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer's disease (AD), but the underlying mechanism remained elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To uncover the mechanisms by which IL-34 provides neuroprotection in AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using senescence-accelerated mouse prone substrain 8 (SAMP8) mice, a well-established model for sporadic AD, we investigated the dynamic changes in brain IL-34 concentrations during AD progression. Afterwards, SAMP8 mice received a 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess the spatial cognitive functions. Neuronal and synaptic markers, oxidative stress makers, pro-inflammatory cytokines and glial activation markers in the brains of SAMP8 mice were measured. Finally, amyloid-\u03b2 (A\u03b2)\n                      <jats:sub>42<\/jats:sub>\n                      -stimulated primary microglia, lentivirus-mediated gene knockdown strategy and co-immunoprecipitation assay were utilized to uncover the possible mechanisms by which IL-34 exerted neuroprotection in AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In SAMP8 mice, we revealed that brain IL-34 concentrations gradually decreased during AD progression. A 4-week continuous intracerebroventricular infusion of IL-34 rescued spatial cognitive impairments, ameliorated neuronal and synaptic damage, and suppressed oxidative stress and microglia-mediated inflammation in the brains of SAMP8 mice. Using A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      -stimulated primary microglia, we demonstrated for the first time that IL-34 suppressed microglial NLRP3 inflammasome activation and pro-inflammatory cytokines release by interacting with triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial functions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings uncover the mechanisms by which IL-34 provides neuroprotection in AD, indicating that IL-34\/TREM2 signaling may represent a novel therapeutic strategy for this devastating disease.<\/jats:p>\n                  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