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Influence of Matrix Metallopeptidase 9 on Beta-Amyloid Elimination Across the Blood-Brain Barrier

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Abstract

Lipoprotein receptor transport across the blood-brain barrier (BBB) mediates beta-amyloid (Aβ) accumulation in the brain and may be a contributing factor in Alzheimer’s disease (AD) pathogenesis. Lipoprotein receptors are susceptible to proteolytic shedding at the cell surface, which precludes the endocytic transport of ligands. A ligand that closely interacts with the lipoprotein receptors is apolipoprotein E (apoE), which exists as three isoforms (apoE2, apoE3, apoE4). Our prior work showed an inverse relationship between lipoprotein receptor shedding and Aβ transport across the BBB, which was apoE-isoform dependent. To interrogate this further, the current studies investigated an enzyme implicated in lipoprotein receptor shedding, matrix metalloproteinase 9 (MMP9). Treatment with MMP9 dose-dependently elevated lipoprotein receptor shedding in brain endothelial cells and freshly isolated mouse cerebrovessels. Furthermore, treatment with a MMP9 inhibitor (SB-3CT) mitigated Aβ-induced lipoprotein receptor shedding in brain endothelial cells and the brains of apoE4 animals. In terms of BBB transit, SB-3CT treatment increased the transport of Aβ across an in vitro model of the BBB. In vivo, administration of SB-3CT to apoE4 animals significantly enhanced Aβ clearance from the brain to the periphery following intracranial administration of Aβ. The current studies show that MMP9 impacts lipoprotein receptor shedding and Aβ transit across the BBB, in an apoE  isoform-specific manner. In total, MMP9 inhibition can facilitate Aβ clearance across the BBB, which could be an effective approach to lowering Aβ levels in the brain and mitigating the AD phenotype, particularly in subjects carrying the apoE4 allele.

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Acknowledgments

We would like to thank the Roskamp Foundation for their generosity in helping to make this work possible.

Funding

This work was supported by Merit Review award number I01BX002839 from the United States (U.S.) Department of Veterans Affairs (VA) Biomedical Laboratory Research and Development Program. The research in this publication was also supported by the National Institute on Aging of the National Institutes of Health under award number R01AG041971.

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Authors and Affiliations

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

    Ben Shackleton, Charis Ringland, Laila Abdullah, Michael Mullan, Fiona Crawford & Corbin Bachmeier

  2. The Open University, Milton Keynes, UK

    Ben Shackleton, Charis Ringland, Laila Abdullah, Michael Mullan, Fiona Crawford & Corbin Bachmeier

  3. James A. Haley Veterans’ Hospital, Tampa, FL, USA

    Laila Abdullah & Fiona Crawford

  4. Bay Pines VA Healthcare System, Bay Pines, FL, USA

    Corbin Bachmeier

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  1. Ben Shackleton
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Correspondence to Corbin Bachmeier.

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Dr. Bachmeier is a Research Scientist at the Bay Pines VA Healthcare System, Bay Pines, FL.

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Shackleton, B., Ringland, C., Abdullah, L. et al. Influence of Matrix Metallopeptidase 9 on Beta-Amyloid Elimination Across the Blood-Brain Barrier. Mol Neurobiol 56, 8296–8305 (2019). https://doi.org/10.1007/s12035-019-01672-z

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