Pterostilbene participates in TLR4- mediated inflammatory response and autophagy-dependent Aβ1–42 endocytosis in Alzheimer's disease

Alzheimer's disease (AD), the most prevalent form of dementia, remains untreatable. One of the factors that contributes to its progression is microglia-mediated inflammation. Pterostilbene, a compound isolated from Chinese dragon's blood, can reduce inflammation caused by overactive microglia. However, its effects on AD transgenic animals and the possible underlying mechanism remain unknown.We evaluated the effect of pterostilbene on learning and memory difficulties in transgenic APP/PS1 mice. We used immunofluorescence to detect microglial activation and Aβ aggregation. We explored the cellular mechanism of pterostilbene by establishing LPS- stimulated BV2 cells and oAβ1-42- exposed HEK 293T cells that overexpress TLR4 and/or MD2 via lentivirus. We applied flow cytometry and immunoprecipitation to examine how pterostilbene regulates TLR4 signaling.Pterostilbene enhanced the learning and memory abilities of APP/PS1 mice and reduced microglial activation and Aβ aggregation in their hippocampus. Pterostilbene alleviated oAβ1-42-induced inflammation, which required the involvement of MD2. Pterostilbene disrupted the binding between TLR4 and MD2, which may further prevent TLR4 dimerization and subsequent inflammatory response. Moreover, pterostilbene restored the impaired endocytosis of oAβ1-42 through an autophagy-dependent mechanism.This is the first demonstration that pterostilbene can potentially treat AD by blocking the interaction of TLR4 and MD2, thereby suppressing TLR4-mediated inflammation.