title: BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.
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.
authors.affiliation: Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany drivak@yahoo.com stefan.liebner@kgu.de.
authors.forename: Kavi
authors.initials: K
authors.lastname: Devraj
authors.affiliation: Orgentec GmbH, Mainz, Germany.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Poznanovic
authors.affiliation: Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Spahn
authors.affiliation: Orgentec GmbH, Mainz, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schwall
authors.affiliation: Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Antoniello
authors.affiliation: AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.affiliation: AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.affiliation: Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Heilemann
authors.affiliation: Dept of Physiology/Biophysics, University of Health Sci./Chicago Medical School, Illinois, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hawkins
authors.affiliation: Pivot GmbH, Trier, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Schrattenholz
authors.affiliation: Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism; D061251:Primary Cell Culture; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer’s disease; BACE-1; blood–brain barrier; endothelium; β-amyloid