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

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

Author information

1
Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany drivak@yahoo.com stefan.liebner@kgu.de.
2
Orgentec GmbH, Mainz, Germany.
3
Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.
4
Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.
5
AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.
6
Dept of Physiology/Biophysics, University of Health Sci./Chicago Medical School, Illinois, USA.
7
Pivot GmbH, Trier, Germany.

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.

KEYWORDS:

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

PMID:
26661166
PMCID:
PMC4929696
DOI:
10.1177/0271678X15606463
[Indexed for MEDLINE]
Free PMC Article

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