Triad3A-Dependent TLR4 Ubiquitination and Degradation Contributes to the Anti-Inflammatory Effects of Pterostilbene on Vascular Dementia

Pterostilbene, a methylated stilbene derived from many plant foods, has significant anti-inflammatory activity. Meanwhile, vascular dementia (VaD) is the second most common subtype of dementia, in which inflammation is one of the major pathogenic contributors. However, the protective effect of pterostilbene on VaD is not well understood. In this work, we investigated the effect of pterostilbene on VaD and explored its underlying mechanisms using in vivo and in vitro models. Y-maze and Morris water maze tests showed pterostilbene-attenuated cognitive impairment in mice with bilateral common carotid artery occlusion (BCCAO). The hippocampal neuronal death and microglial activation in BCCAO mice were also reduced by pterostilbene treatment. Further, pterostilbene inhibited the expression of TLR4 and downstream inflammatory cytokines in these mice, with similar results observed in an oxygen-glucose deprivation and reperfusion (OGD/R) BV-2 cell model. In addition, its anti-inflammatory effect on OGD/R BV-2 cells was partially blocked by TLR4 overexpression. Moreover, Triad3A-TLR4 interactions were increased by pterostilbene following enhanced ubiquitination and degradation of TLR4, and the inhibitory effect of pterostilbene on inflammation was blocked by Triad3A knockdown in OGD/R-stimulated BV-2 cells. Together, these results reveal that pterostilbene could reduce vascular cognitive impairment and that Triad3A-mediated TLR4 degradation might be the key target.