Notch/NF-κB crosstalk signaling controls SASP gene expression during brain aging
4 affiliations
- 1University Hospital Ulm, Department of Internal Medicine I , Albert-Einstein-Allee 23, 89081 Ulm ,
- 2Department of Neurology, The Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou 215002 ,
- 3University of Ulm, Institute for Physiological Chemistry , Albert-Einstein-Allee 11, 89081 Ulm ,
- 4Justus-Liebig-University Giessen, Institute of Biochemistry , Friedrichstrasse 24, 35392 Giessen ,
Abstract
Brain aging is associated with chronic, low-grade inflammation known as inflammaging, which is largely driven by senescent glial cells secreting pro-inflammatory factors termed as senescence-associated secretory phenotype (SASP). In humans, the release of SASP factors in the brain is linked with an increased risk for the development of neurodegenerative disorders; thus, elucidating the underlying molecular mechanisms is essential for understanding the pathophysiology of brain aging. Both NF-κB and Notch signaling are known to regulate SASP expression; however, their mode of interaction in brain inflammaging is poorly understood. Here, we demonstrate that brain aging is broadly associated with NF-κB activation but Notch suppression using different transgenic mouse models. Astrocytic NF-κB activation in young mice was able to mimic premature SASP formation but repressed Notch signaling in parallel. Bioinformatic analyses further identified conserved crosstalk sites within SASP genes co-occupied by Notch/RBPJ and NF-κB transcription factors in vivo, allowing specific combinatorial regulation. Importantly, selective physical interactions enable that activated Notch can act as a negative modulator of NF-κB signaling at different molecular levels. Consistently, pharmacological activation of Notch in primary astrocytes significantly reduced NF-κB-driven SASP gene expression. Together, these findings identify Notch–NF-κB crosstalk as a potential therapeutic target to mitigate brain inflammaging.
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BibTeX
@article{yang2026notchnfκb,
title = {{Notch/NF-κB crosstalk signaling controls SASP gene expression during brain aging}},
author = {Qingwen Yang and Hina Zarrin and Tabea Hein and Burak Yildiz and Vivien Prex and Konstantinos Siontas and Tilman Borggrefe and Benedetto Daniele Giaimo and Tobias Friedrich and M Lienhard Schmitz and Thomas Wirth and Franz Oswald and Bernd Baumann},
journal = {Nucleic Acids Research},
year = {2026},
month = nov,
doi = {10.1093/nar/gkag1110},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1110/9013032},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Notch/NF-κB crosstalk signaling controls SASP gene expression during brain aging
AU - Qingwen Yang
AU - Hina Zarrin
AU - Tabea Hein
AU - Burak Yildiz
AU - Vivien Prex
AU - Konstantinos Siontas
AU - Tilman Borggrefe
AU - Benedetto Daniele Giaimo
AU - Tobias Friedrich
AU - M Lienhard Schmitz
AU - Thomas Wirth
AU - Franz Oswald
AU - Bernd Baumann
PY - 2026
DA - 2026/11/05
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1110
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1110/9013032
AB - Brain aging is associated with chronic, low-grade inflammation known as inflammaging, which is largely driven by senescent glial cells secreting pro-inflammatory factors termed as senescence-associated secretory phenotype (SASP). In humans, the release of SASP factors in the brain is linked with an increased risk for the development of neurodegenerative disorders; thus, elucidating the underlying molecular mechanisms is essential for understanding the pathophysiology of brain aging. Both NF-κB and Notch signaling are known to regulate SASP expression; however, their mode of interaction in brain inflammaging is poorly understood. Here, we demonstrate that brain aging is broadly associated with NF-κB activation but Notch suppression using different transgenic mouse models. Astrocytic NF-κB activation in young mice was able to mimic premature SASP formation but repressed Notch signaling in parallel. Bioinformatic analyses further identified conserved crosstalk sites within SASP genes co-occupied by Notch/RBPJ and NF-κB transcription factors in vivo, allowing specific combinatorial regulation. Importantly, selective physical interactions enable that activated Notch can act as a negative modulator of NF-κB signaling at different molecular levels. Consistently, pharmacological activation of Notch in primary astrocytes significantly reduced NF-κB-driven SASP gene expression. Together, these findings identify Notch–NF-κB crosstalk as a potential therapeutic target to mitigate brain inflammaging.
SN - 0305-1048
SN - 1362-4962
ER -