Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer's Disease in Late Life

Hyperbilirubinemia may increase the risk of Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased A beta production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several protein kinases (GSK-3 beta, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of A beta PP gamma-secretase PS2 and decreased the expression of alpha-secretase ADAM17, which were positively correlated with A beta production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD.