APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β

  • Nat Aging. 2021 Jun;1(6):506-520. doi: 10.1038/s43587-021-00073-z.
Axel Montagne  1  2 ,  Angeliki M Nikolakopoulou  1  2 ,  Mikko T Huuskonen  1  2 ,  Abhay P Sagare  1  2 ,  Erica J Lawson  1 ,  Divna Lazic  1 ,  Sanket V Rege  1 ,  Alexandra Grond  1 ,  Edward Zuniga  1 ,  Samuel R Barnes  3 ,  Jacob Prince  1 ,  Meghana Sagare  1 ,  Ching-Ju Hsu  1 ,  Mary J LaDu  4 ,  Russell E Jacobs  1 ,  Berislav V Zlokovic  1
Affiliations
  • 1. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 2. These authors contributed equally: Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare.
  • 3. Department of Radiology, Loma Linda University, Loma Linda, CA, USA.
  • 4. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
PMID: 35291561 DOI: 10.1038/s43587-021-00073-z
Abstract

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, Amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged apoE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of Amyloid-β. BBB breakdown was associated with activation of the Cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on Amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the Cyclophilin A pathway in pericytes independently of Amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.

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