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

Haoyu Chen, Lu Liang, Hua Xu, Jia Xu, Leyi Yao, Yanling Li, Yufan Tan, Xiaofen Li, Qingtian Huang, Zhenjun Yang, Jiawen Wu, Jinghong Chen, Hongbiao Huang, Xuejun Wang, Chang E. Zhang, Jinbao Liu

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ-secretase PS2 and decreased the expression of α-secretase ADAM17, which were positively correlated with Aβ 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.

Original languageEnglish (US)
Pages (from-to)277-295
Number of pages19
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - 2020


  • Alzheimer's disease
  • AβPP
  • amyloid-β
  • bilirubin
  • protein kinase
  • spatial learning and memory injury
  • tau hyperphosphorylation
  • tau protein
  • α-secretase
  • γ-secretase

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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