Carnosic Acid Reverses the Inhibition of ApoE4 on Cell Surface Level of ApoER2 and Reelin Signaling Pathway

Article type: Research Article

Authors: Feng, Maoxiao^a | Cui, Donghai^a | Li, Yi^b | Shi, Jian^c | Xiang, Lan^d | Bian, Hong^e | Ma, Zhiyong^f | Xia, Wen^{b; *} | Wei, Guangwei^{a; *}

Affiliations: [a] Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China | [b] Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong, China | [c] Department of Neurology, Department of Veterans Affairs Medical Center, San Francisco and University of California, San Francisco, CA, USA | [d] School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China | [e] Department of Neurology, Jinan Central Hospital, Shandong University, Jinan, Shandong, China | [f] The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, China

Correspondence: [*] Correspondence to: Wen Xia, Department of Neurology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012 Shandong, China. Tel.: +86-18560085503; E-mail: xiawen_2014@sina.cn and Guangwei Wei, Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012 Shandong, China. Tel.: +86 0531 88382308; E-mail: gwwei@yahoo.com.

Abstract: The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer’s disease (AD) mouse model. However, there are few reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin 17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD.

Keywords: Apolipoprotein E receptor 2, Apolipoprotein E4, carnosic acid, Reelin signaling pathway, sorting nexin 17

DOI: 10.3233/JAD-190914

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 517-528, 2020