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Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing

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Abstract

Recent findings indicate an isoform-specific role for apolipoprotein E (apoE) in the elimination of beta-amyloid (Aβ) from the brain. ApoE is closely associated with various lipoprotein receptors, which contribute to Aβ brain removal via metabolic clearance or transit across the blood–brain barrier (BBB). These receptors are subject to ectodomain shedding at the cell surface, which alters endocytic transport and mitigates Aβ elimination. To further understand the manner in which apoE influences Aβ brain clearance, these studies investigated the effect of apoE on lipoprotein receptor shedding. Consistent with prior reports, we observed an increased shedding of the low-density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1) following Aβ exposure in human brain endothelial cells. When Aβ was co-treated with each apoE isoform, there was a reduction in Aβ-induced shedding with apoE2 and apoE3, while lipoprotein receptor shedding in the presence of apoE4 remained increased. Likewise, intracranial administration of Aβ to apoE-targeted replacement mice (expressing the human apoE isoforms) resulted in an isoform-dependent effect on lipoprotein receptor shedding in the brain (apoE4 > apoE3 > apoE2). Moreover, these results show a strong inverse correlation with our prior work in apoE transgenic mice in which apoE4 animals showed reduced Aβ clearance across the BBB compared to apoE3 animals. Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing Aβ from the brain.

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Acknowledgments

We would like to thank the laboratory of Dr. Mary Jo LaDu (University of Illinois at Chicago) including Dr. Leon Tai and Susan Wohlgenant for isolating and preparing the mixed glial cultures. Research was supported by the National Institute on Aging of the National Institutes of Health under award number R01AG041971. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Ethical standards

All experimental protocols involving animals were approved by the Institutional Animal Care and Use Committee of the Roskamp Institute, Inc. The manuscript does not contain clinical studies or patient data.

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The authors declare that they have no conflict of interest.

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  1. The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA

    Corbin Bachmeier, Ben Shackleton, Joseph Ojo, Daniel Paris, Michael Mullan & Fiona Crawford

  2. Department of Life Science, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK

    Corbin Bachmeier, Ben Shackleton, Daniel Paris & Fiona Crawford

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  1. Corbin Bachmeier
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Correspondence to Corbin Bachmeier.

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Bachmeier, C., Shackleton, B., Ojo, J. et al. Apolipoprotein E Isoform-Specific Effects on Lipoprotein Receptor Processing. Neuromol Med 16, 686–696 (2014). https://doi.org/10.1007/s12017-014-8318-6

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