Astrocyte regulates neuroinflammation and myelination in BCCAO-related cognitive impairment via the PIAS1-STAT1...

Vascular dementia (VaD) ranks as the second most common form of cognitive impairment worldwide, surpassed only by Alzheimer's disease (AD), yet its pathophysiological mechanisms are still not fully understood. This study sought to explore the mechanisms underlying secondary cognitive decline after transient cerebral ischemia, employing a temporary bilateral common carotid artery occlusion (BCCAO) model to mimic clinical cerebral ischemia-reperfusion (I/R) conditions. Dynamic detection of model mice revealed no significant loss of hippocampal neurons after surgery. Nevertheless, at 12 weeks post-surgery, the mice exhibited obvious myelin loss accompanied by cognitive decline. Further intervention studies showed that the microglial depleter PLX5622 failed to effectively rescue myelin damage and cognitive impairment, while astrocytes remained persistently activated. Analysis of the differential expression profile of astrocytes from a VaD patient brain tissue database identified Protein Inhibitor of Activated STAT1 (PIAS1) as a key regulator, which was significantly downregulated in the astrocytes of VaD patients-this finding was validated in model mice. Behavioral assessments revealed that targeted overexpression of PIAS1 in astrocytes, achieved through adeno-associated viral (AAV) delivery, markedly ameliorated cognitive deficits, attenuated myelin injury, and suppressed astrocytic inflammatory responses. In parallel, in vitro studies using primary astrocyte cultures demonstrated that PIAS1 exerts its anti-inflammatory effects by modulating the signal transducer and activator of transcription 1 (STAT1) signaling pathway. In summary, the findings of this study demonstrate that reduced expression of PIAS1 in astrocytes following mild cerebral ischemia plays a crucial role in triggering secondary cognitive deficits and myelin degeneration. Furthermore, PIAS1 regulates astrocyte-mediated inflammatory responses via a STAT1-dependent pathway, offering new perspectives on the underlying mechanisms of VaD and potential therapeutic interventions.