{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:06:18Z","timestamp":1788195978548,"version":"build-2803163510"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"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. Immunol."],"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Individuals with type 2 diabetes mellitus (T2DM) are at-risk for developing vascular dementia (VaD). Hyperglycemia leads to the activation of astrocytes. These activated cells produce proinflammatory mediators like cytokines or chemokines, that cause cerebrovascular damage. Previous sequencing showed <jats:italic>Pdpn<\/jats:italic>\u2019s high expression in activated stellate cells and possible inflammation involvement. Our study aims to reveal its role in T2DM-induced hippocampal inflammation in VaD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Firstly, we will validate the expression of the <jats:italic>Pdpn<\/jats:italic> gene in T2DM astrocytes via qPCR and Western blot. Subsequently GFAP-specific promoter adeno-associated virus(AAV)carrying interfering sequence was used to knockdown the key gene in astrocytes of T2DM mice. Then the step-down test was conducted to assess the cognition level. The fluorescence intensities of IL-1\u03b2, IL-6, TNF-\u03b1, and TGF-\u03b2 were measured via immunofluorescence assay to assess the level of inflammation in the brain after the key gene knockdown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After the validation of transcriptome sequencing, the <jats:italic>Pdpn<\/jats:italic> gene was identified as a key gene upregulated in astrocytes from T2DM. Comparing to T2DM mice, knocking down <jats:italic>Pdpn<\/jats:italic> in astrocytes extended the latency and decreased the number of errors in T2DM mice, showing improved memory impairment. After the cognition assessment, the mice were euthanized, and the inflammatory factors associated to the VaD were detected by immunofluorescence. We showed that the fluorescence intensities of IL-1\u03b2, IL-6, TNF-\u03b1, and TGF-\u03b21 in hippocampus were decreased after the <jats:italic>Pdpn<\/jats:italic> knocking down in astrocytes of T2DM mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In summary, this study demonstrates that <jats:italic>Pdpn<\/jats:italic> exerts a novel player in T2DM-induced neuroinflammation and cognitive decline. Knocking down <jats:italic>Pdpn<\/jats:italic> in astrocytes shows a protective effect in hippocampal inflammation and VaD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1503807","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T05:20:00Z","timestamp":1737523200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Knockdown of PDPN in astrocytes reduces hippocampal inflammation in T2DM 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