{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Liu C"],"funding":["National Natural Science Foundation of China"],"pagination":["8782"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12469424"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(18)"],"pubmed_abstract":["The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (<i>p</i> < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, <i>p</i> < 0.001; CD86<sup>+</sup> cells decreased by 42%, <i>p</i> < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, <i>p</i> = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, <i>p</i> < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (<i>p</i> < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment."],"journal":["International journal of molecular sciences"],"pubmed_title":["Inhibition of the HMGB1-RAGE Axis Attenuates Microglial Inflammation and Ameliorates Hypoxia-Induced Cognitive Impairment."],"pmcid":["PMC12469424"],"funding_grant_id":["82230063 and 82303493"],"pubmed_authors":["Zou Y","Zhang J","Chen M","Zhang H","Luo W","Liu C","Guan R","Du M"],"additional_accession":[]},"is_claimable":false,"name":"Inhibition of the HMGB1-RAGE Axis Attenuates Microglial Inflammation and Ameliorates Hypoxia-Induced Cognitive Impairment.","description":"The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (<i>p</i> < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, <i>p</i> < 0.001; CD86<sup>+</sup> cells decreased by 42%, <i>p</i> < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, <i>p</i> = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, <i>p</i> < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (<i>p</i> < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-05-01T03:21:29.484Z","creation":"2026-05-01T03:11:14.675Z"},"accession":"S-EPMC12469424","cross_references":{"pubmed":["41009351"],"doi":["10.3390/ijms26188782"]}}