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bioRxiv · 10.64898/2026.08.27.745197

Dysregulated splenic glucocorticoid sensitivity in aging and an α-synuclein transgenic mouse model of Parkinson's disease

Rombach, D.·Bopp, V.·Langgartner, D.·Grozdanov, V.·Kassubek, J.·Touma, C.·Reber, S. O.·Danzer, K. M.
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Abstract

Introduction: Parkinson's disease (PD) and aging both disrupt hypothalamic-pituitary-adrenal (HPA) axis function and peripheral immune homeostasis. Whether aging or -synuclein (-syn) pathology alters glucocorticoid (GC) sensitivity of peripheral immune cells has not been investigated. Methods: Using an ex vivo GC sensitivity assay, we assessed the responsiveness of isolated and lipopolysaccharide (LPS)-stimulated splenocytes to the anti-inflammatory effects of increasing doses of corticosterone (CORT) in a wild-type (WT) aging cohort and in a PD -syn transgenic mouse model and respective age-matched controls. Results: Compared with splenocytes from 6-month-old WT mice, splenocytes from 20-month-old WT mice were less sensitive to 0.1 and 0.5 M CORT. Isolated splenocytes from PD vs. control mice were less sensitive to 0.05, 0.1, and 0.5 M CORT specifically at 16 months of age, but not at 6 or 20 months of age. As peripheral immune phenotyping revealed neither differences in HPA axis-related parameters nor in splenic GC receptor expression between PD and age-matched control mice at 6, 16, and 20 months, splenic GC resistance in PD mice at 16 months of age seems to be mediated by downstream GR signaling dysfunction. Conclusion: Together, our results support the hypothesis that -syn pathology accelerates an aging-associated decline in the peripheral sensitivity to anti-inflammatory GCs and may thereby sustain systemic and neuroinflammatory processes in PD.

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Rombach, D., Bopp, V., Langgartner, D., Grozdanov, V., Kassubek, J., Touma, C., Reber, S. O., Danzer, K. M.. 2026-09-01. Dysregulated splenic glucocorticoid sensitivity in aging and an α-synuclein transgenic mouse model of Parkinson's disease. https://doi.org/10.64898/2026.08.27.745197

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