Bilberry anthocyanin improves the neuroinflammation and cognitive disfunctions in APP/PSEN1 mice via the CD33/TREM2/TYROBP signaling pathway in microglia

Alzheimer’s disease, characterized by neuroinflammation and beta-amyloid protein plaques, is a memory-threatening neurodegenerative disease with no effective treatments. Here, the effect of bilberry anthocyanin (BA) on cognitive functions was evaluated using APP/PSEN1 transgenic Alzheimer’s disease model mice and their WT littermates. Our results revealed that BA appreciably improves learning and memory abilities and reverses defects to cognitive functions in APP/PSEN1 mice. Furthermore, BA reverses brain, liver and kidney damages caused by Alzheimer's disease, with no significant changes in oxidative stress and lipid metabolism-related indicators. In addition, BA decreases serum and brain lipopolysaccharides (LPS) levels and increases fecal short-chain fatty acids content. Immunofluorescence and RT-PCR analyses results showed that BA fully activates the microglia and astrocytes, downregulates the expression of inflammatory factors (TNF-a, NF-Kβ, IL-1β, IL-6, COX-2, iNOS and CD33) and chemokine receptor CX3CR1, and upregulates the expression of microglia homeostatic factors (TREM2 and TYROBP) and Toll-likem (TLR2 and TLR4). Moreover, Western blot analysis revealed that BA significantly upregulates the expression of synaptic and phagocytotic function-related proteins (CD68 and IRF7) in APP/PSEN1 mice. Altogether, we show for the first time that BA consumption reverses Alzheimer’s disease‑induced cognitive disfunction, decreases hippocampal neuroinflammatory responses, and induces phagocytosis of microglia to beta-amyloid protein plaques by regulating the CD33/TREM2/TYROBP signaling pathway in microglia.