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      Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

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          Abstract

          The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 ( APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD ( APOE4 > APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

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          Author and article information

          Journal
          J Cereb Blood Flow Metab
          J. Cereb. Blood Flow Metab
          JCB
          spjcb
          Journal of Cerebral Blood Flow & Metabolism
          SAGE Publications (Sage UK: London, England )
          0271-678X
          1559-7016
          January 2016
          January 2016
          : 36
          : 1 , JCBFM Clinical issue: Impact of small vessel disease on cognition
          : 216-227
          Affiliations
          [1 ]Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
          [2 ]Department of Physiology and Biophysics, Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
          [3 ]Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
          [4 ]Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
          Author notes
          [*]

          These authors contributed equally to the work.

          [*]Berislav V Zlokovic, Department of Physiology and Biophysics, Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, ZNI 101, Los Angeles, California 90089-2821, USA. Email: Zlokovic@ 123456usc.edu
          Article
          PMC4758554 PMC4758554 4758554 10.1038_jcbfm.2015.44
          10.1038/jcbfm.2015.44
          4758554
          25757756
          62a8e2db-022b-44e3-acfa-cdbb6c95683f
          © The Author(s) 2015
          History
          : 19 November 2014
          : 3 February 2015
          : 5 February 2015
          Categories
          Original Articles

          neurovascular unit,Alzheimer’s,pericytes,blood–brain barrier,neurodegeneration

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