SerpinA3N Regulates the Secretory Phenotype of Mouse Senescent Astrocytes Contributing to Neurodegeneration.

Senescent astrocyte accumulation in the brain during normal aging is a driver of age-related neurodegenerative diseases such as Alzheimer's disease. However, the molecular events underlying astrocyte senescence in Alzheimer's disease are not fully understood. In this study, we demonstrated that senescent astrocytes display a secretory phenotype known as the senescence-associated secretory phenotype (SASP), which is associated with the upregulation of various proinflammatory factors and the downregulation of neurotrophic growth factors (eg, NGF and BDNF), resulting in a decrease in astrocyte-mediated neuroprotection and increased risk of neurodegeneration. We found that SerpinA3N is upregulated in senescent primary mouse astrocytes after serial passaging in vitro or by H2O2 treatment. Further exploration of the underlying mechanism revealed that SerpinA3N deficiency protects against senescent astrocyte-induced neurodegeneration by suppressing SASP-related factors and inducing neurotrophic growth factors. Brain tissues from Alzheimer's disease model mice possessed increased numbers of senescent astrocytes. Moreover, senescent astrocytes exhibited upregulated SerpinA3N expression in vitro and in vivo, confirming that our cell model recapitulated the in vivo pathology of these neurodegenerative diseases. Altogether, our study reveals a novel molecular strategy to regulate the secretory phenotype of senescent astrocytes and implies that SerpinA3N and its regulatory mechanisms may be potential targets for delaying brain aging and aging-related neurodegenerative diseases. © The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Xiaojuan Han, Qing Lei, Huanhuan Liu, Tianying Zhang, Xingchun Gou. SerpinA3N Regulates the Secretory Phenotype of Mouse Senescent Astrocytes Contributing to Neurodegeneration. The journals of gerontology. Series A, Biological sciences and medical sciences. 2024 Apr 01;79(4)

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PMID: 38175667

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