The Senescent Phenotype of Cultured Hypothalamic Astrocytes from Rats with Streptozotocin-Induced Dementia

Alzheimer's disease (AD) is the most prevalent form of dementia, with aging as its primary risk factor. Among experimental models of sporadic AD, intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents is widely used. We hypothesized that STZ accelerates the process of cellular senescence, which in astrocytes can be assessed using classic markers, including p16, β-galactosidase, Lamin B1, and the senescence-associated secretory phenotype (SASP). To explore this, we cultured hypothalamic astrocytes from adult male Wistar rats at four weeks after STZ-ICV model induction to investigate whether the astroglial changes observed in vivo were maintained under in vitro conditions, and whether markers of senescence were more evident in astrocytes from STZ animals. As in the STZ dementia model, astrocyte cultures exhibited reduced levels of glutamine synthetase and glutathione. Furthermore, elevations in the transcription factors, FOXO3a, Nrf2, and NF-κB, were observed. Markers of unfolded protein response (CHOP and sorcin) were also increased in astrocytes from STZ animals. When evaluating senescence parameters, increases in p53, p21, and p16 were observed, while Lamin B1 levels remained unchanged. With regard to SASP, modulations in TNFα and extracellular HMGB1 and S100B levels also suggested the induction of a senescent profile. Taken together, these findings demonstrate that cultured astrocytes retain key alterations observed in the in vivo model of STZ-induced dementia, highlighting its usefulness for studying AD and therapeutic strategies. Observations in cultures suggest that STZ indeed induces astrocyte senescence and that S100B may be included as a component of the astroglial SASP.