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

Abstract

Background: Hyperbilirubinemia may increase the risk of Alzheimer's disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Methods: Three animal models and primary hippocampal cells were used to explore in this study: (1) acute bilirubin treatment; (2) lateral ventricle injection; (3) long term observation. Results: 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 APP 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 cells. Conclusions: Bilirubin may be an upstream activator to induce AD, and bilirubin encephalopathy is an AD-like disease. Funding Statement: The study was supported in part by the National High Technology Research and Development Program of China (2006AA02Z4B5); the National Natural Science Foundation of China(81170608, 81570278, 81602427, 81600089, 81670156); the Science and Technology Program of Guangzhou (201707010046, 201604020001); The National Funds for Developing Local Colleges and Universities (B16056001); Natural Science Foundation research team of Guangdong Province (2018B030312001); Guangzhou Education System (1201610014, 1201620494); Natural Science Foundation of Guangdong Province (2017A030313662). Declaration of Interests: All authors declare that there are no conflicts of interest. Ethics Approval Statement: The protocol for the care and use of all animals in this study was in accordance with the Guangdong Animal Center for the ethical treatment of animals and approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University (SYXK2016-0168, Guangzhou, China).