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

Article type: Research Article

Authors: Chen, Haoyu^{a; 1} | Liang, Lu^{a; 1} | Xu, Hua^{a; 1} | Xu, Jia^a | Yao, Leyi^a | Li, Yanling^a | Tan, Yufan^a | Li, Xiaofen^a | Huang, Qingtian^a | Yang, Zhenjun^a | Wu, Jiawen^a | Chen, Jinghong^a | Huang, Hongbiao^a | Wang, Xuejun^b | Zhang, Chang-E.^{a; *} | Liu, Jinbao^{a; *}

Affiliations: [a] Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Lab of Respiratory Disease, School of Basic Medical Sciences, Affiliated Cancer Hospital of Guangzhou Medical University, Guangdong, People’s Republic of China | [b] Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA

Correspondence: [*] Correspondence to: Jinbao Liu, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, SKLRD, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R.C. Tel.: +8620 37103007; Fax: +8620 37103099; E-mail: [email protected]. and C.-E. Zhang, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R.C. Tel.: +8620 37103636; Fax: +8620 37103099; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: AβPP, α-secretase, Alzheimer’s disease, amyloid-β, bilirubin, γ-secretase, protein kinase, spatial learning and memory injury, tau hyperphosphorylation, tau protein

DOI: 10.3233/JAD-190945

Journal: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 277-295, 2020