Timosaponin B-II attenuates hemorrhagic transformation-driven acceleration of alzheimer disease-related pathology after ischemic stroke.

Hemorrhagic transformation (HT) is a major complication of reperfusion therapy after ischemic stroke, but its impact on Alzheimer disease (AD) progression remains unclear. In this study, we used an early-stage APP/PS1 mouse model and found that HT following transient middle cerebral artery occlusion(tMCAO) aggravated cognitive impairment and promoted AD-like pathological changes, which were markedly attenuated by Timosaponin B-II (TB-II) treatment. TB-II effectively alleviated HT following tMCAO(tMCAO/HT)-induced cognitive and recognition memory deficits in APP/PS1 mice and reduced hippocampal Aβ42 production. In vitro, TB-II pretreatment reversed oxygen-glucose deprivation/reoxygenation (OGD/R) and hemin-induced increases in Aβ42 production and apoptotic propensity, as well as decreases in mitochondrial membrane potential and cell viability in N2a/APPswe cells. Mechanistically, TB-II activated NRF2, which in turn indirectly modulating GSK-3β-mediated APP phosphorylation and negatively regulated BACE1 transcription through binding promoter binding, ultimately suppressing amyloidogenic processing. Together, our findings suggest that TB-II may serve as a potential therapeutic agent against HT-associated acceleration of AD-like pathology after ischemia-reperfusion.