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Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

Nature volume 485, pages 512–516 (2012)Cite this article

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Abstract

Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE41. APOE4 is a major genetic risk factor for Alzheimer’s disease2,3 and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage3. Neurovascular dysfunction is present in normal APOE4 carriers4,5,6 and individuals with APOE4-associated disorders3,7,8,9,10. In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown11,12, whereas APOE4 increases BBB susceptibility to injury13. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.

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Figure 1: CypA deficiency or inhibition reverses BBB breakdown in Apoe − / − and APOE4 mice.
Figure 2: CypA activates the NF-κB–MMP9 pathway causing BBB breakdown in Apoe − / − and APOE4 mice.
Figure 3: CypA ablation or inhibition reverses microvascular and CBF reductions in Apoe − / − and APOE4 mice.
Figure 4: APOE isoform-specific regulation of CypA–NF-κB–MMP9 pathway in pericytes.
Figure 5: Vascular defects in Apoe − / − and APOE4 mice precede neuronal dysfunction.

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Acknowledgements

We would like to thank the National Institute of Health for grants R37NS34467 (B.V.Z.); R37AG23084 (B.V.Z.); RO1AG039452 (B.V.Z.); and R37AG13956 (D.M.H.) used to support this study.

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Authors and Affiliations

  1. Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, 14642, New York, USA

    Robert D. Bell, Ethan A. Winkler, Itender Singh, Abhay P. Sagare, Rashid Deane, Zhenhua Wu, Jan Sallstrom & Berislav V. Zlokovic

  2. Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, 14642, New York, USA

    Robert D. Bell & Bradford C. Berk

  3. Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, Saint Louis, 63110, Missouri, USA

    David M. Holtzman

  4. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171 77, Sweden,

    Christer Betsholtz & Annika Armulik

  5. Institute of Neuropathology, University Hospital Zürich, CH-8091, Zürich, Switzerland ,

    Annika Armulik

  6. Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Center for Neurodegeneration and Regeneration, University of Southern California, Keck School of Medicine, Los Angeles, 90089, California, USA

    Berislav V. Zlokovic

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  1. Robert D. Bell
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Contributions

R.D.B. designed and performed experiments, analysed data and contributed to writing the paper. E.A.W. designed and performed experiments. I.S. performed experiments. A.P.S. performed CBF experiments. R.D. designed experiments and analysed data. Z.W. gathered pilot data. D.M.H. provided guidance and edited the paper. C.B. designed experiments and edited the paper. A.A. performed pilot cadaverine studies. J.S. generated pilot data. B.C.B. provided guidance and edited the paper. B.V.Z. designed experiments, analysed data and wrote the paper.

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Correspondence to Berislav V. Zlokovic.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-15, Supplementary Materials and Methods, Supplementary Discussion, Supplementary Tables 1-3 and Supplementary References. (PDF 1515 kb)

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Bell, R., Winkler, E., Singh, I. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012). https://doi.org/10.1038/nature11087

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