BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease

J Cereb Blood Flow Metab. 2016 Jul;36(7):1281-94. doi: 10.1177/0271678X15606463. Epub 2015 Oct 13.


Endothelial cells of the blood-brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood-brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer's disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood-brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D-dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer's disease mouse model we show that BACE-1 is upregulated at the blood-brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood-brain barrier in β-amyloid generation and in vascular aspects of Alzheimer's disease, particularly in the development of cerebral amyloid angiopathy.

Keywords: Alzheimer’s disease; BACE-1; blood–brain barrier; endothelium; β-amyloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Aspartic Acid Endopeptidases / genetics*
  • Blood-Brain Barrier / metabolism*
  • Blotting, Western
  • Cattle
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / metabolism*
  • Humans
  • Immunohistochemistry
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microvessels / metabolism
  • Primary Cell Culture
  • Real-Time Polymerase Chain Reaction


  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse