Iron Regulates Apolipoprotein E Expression and Secretion in Neurons and Astrocytes

Article type: Research Article

Authors: Xu, He^{a; b} | Perreau, Victoria M.^a | Dent, Krista A.^a | Bush, Ashley I.^a | Finkelstein, David I.^{a; 1} | Adlard, Paul A.^{a; *; 1}

Affiliations: [a] The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia | [b] The Department of Tissue Engineering, School of Fundamental Science, China Medical University, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China

Correspondence: [*] Correspondence to: Paul Adlard, 30 Royal Parade, Parkville, 3052, Victoria, Australia. Tel.: +61 3 90356775; +61 3 9035 6680; Fax: +61 3 90353103; E-mail: [email protected].

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

Abstract: Background:There is strong evidence that iron homeostasis is impaired in the aging and Alzheimer’s disease (AD) brain and that this contributes to neurodegeneration. Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for AD. However, the interaction between the two has yet to be fully explored. Objective:This study aimed to investigate the relationship between exogenous iron levels and ApoE in neurons and astrocytes. Methods:Our study used primary cultured cortical neurons and astrocytes to investigate the changes in ApoE caused by iron. Western blot and RT-PCR were used to measure ApoE. Results:We observed that iron upregulated intracellular ApoE levels in both neurons and astrocytes at the post-transcriptional and transcriptional level, respectively. However, there was less full-length ApoE secreted by neurons and astrocytes after iron treatment. We speculate that this might impair brain lipid metabolism and amyloid-β clearance. In terms of ApoE receptors, we observed that neuronal LRP-1 levels were increased by the addition of exogenous iron, which could contribute to AβPP endocytosis in neurons. However, there were no significant changes in neuronal LDLR, astrocyte LDLR, or astrocyte LRP-1. Conclusion:Our study reveals that iron may contribute to the pathogenesis of AD by affecting ApoE and its receptors and supports the notion that iron chelation should be investigated as a therapeutic strategy for AD.

Keywords: Apolipoprotein E, iron, lipoprotein receptor-related protein, low-density lipoprotein receptor

DOI: 10.3233/JAD-150797

Journal: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 471-487, 2016