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

Kavi Devraj*, Slobodan Poznanovic, Christoph Spahn, Gerhard Schwall, Patrick N. Harter, Michel Mittelbronn, Katia Antoniello, Paolo Paganetti, Andreas Muhs, Mike Heilemann, Richard A. Hawkins, André Schrattenholz, Stefan Liebner

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1281-1294
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume36
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016
Externally publishedYes

Keywords

  • Alzheimer's disease
  • BACE-1
  • blood-brain barrier
  • endothelium
  • β-amyloid

Fingerprint

Dive into the research topics of 'BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this