BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.
Identifieur interne : 000174 ( Main/Exploration ); précédent : 000173; suivant : 000175BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.
Auteurs : Kavi Devraj [Allemagne] ; Slobodan Poznanovic [Allemagne] ; Christoph Spahn [Allemagne] ; Gerhard Schwall [Allemagne] ; Patrick N. Harter [Allemagne] ; Michel Mittelbronn [Allemagne] ; Katia Antoniello [Suisse] ; Paolo Paganetti [Suisse] ; Andreas Muhs [Suisse] ; Mike Heilemann [Allemagne] ; Richard A. Hawkins [États-Unis] ; André Schrattenholz [Allemagne] ; Stefan Liebner [Allemagne]Source :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [ 1559-7016 ] ; 2016.
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.
DOI: 10.1177/0271678X15606463
PubMed: 26661166
Affiliations:
- Allemagne, Suisse, États-Unis
- Canton de Vaud, District de Darmstadt, Hesse (Land), Illinois, Rhénanie-Palatinat
- Francfort-sur-le-Main, Lausanne, Mayence
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Harter</name><affiliation wicri:level="3"><nlm:affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Mittelbronn, Michel" sort="Mittelbronn, Michel" uniqKey="Mittelbronn M" first="Michel" last="Mittelbronn">Michel Mittelbronn</name><affiliation wicri:level="3"><nlm:affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Antoniello, Katia" sort="Antoniello, Katia" uniqKey="Antoniello K" first="Katia" last="Antoniello">Katia Antoniello</name><affiliation wicri:level="3"><nlm:affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>AC Immune SA, PSE-B EPFL, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Paganetti, Paolo" sort="Paganetti, Paolo" uniqKey="Paganetti P" first="Paolo" last="Paganetti">Paolo Paganetti</name><affiliation wicri:level="3"><nlm:affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>AC Immune SA, PSE-B EPFL, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Muhs, Andreas" sort="Muhs, Andreas" uniqKey="Muhs A" first="Andreas" last="Muhs">Andreas Muhs</name><affiliation wicri:level="3"><nlm:affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>AC Immune SA, PSE-B EPFL, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Heilemann, Mike" sort="Heilemann, Mike" uniqKey="Heilemann M" first="Mike" last="Heilemann">Mike Heilemann</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Hawkins, Richard A" sort="Hawkins, Richard A" uniqKey="Hawkins R" first="Richard A" last="Hawkins">Richard A. Hawkins</name><affiliation wicri:level="2"><nlm:affiliation>Dept of Physiology/Biophysics, University of Health Sci./Chicago Medical School, Illinois, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Dept of Physiology/Biophysics, University of Health Sci./Chicago Medical School, Illinois</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Schrattenholz, Andre" sort="Schrattenholz, Andre" uniqKey="Schrattenholz A" first="André" last="Schrattenholz">André Schrattenholz</name><affiliation wicri:level="1"><nlm:affiliation>Pivot GmbH, Trier, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Pivot GmbH, Trier</wicri:regionArea><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion></affiliation></author><author><name sortKey="Liebner, Stefan" sort="Liebner, Stefan" uniqKey="Liebner S" first="Stefan" last="Liebner">Stefan Liebner</name><affiliation wicri:level="3"><nlm:affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author></analytic><series><title level="j">Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism</title><idno type="eISSN">1559-7016</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Suisse</li><li>États-Unis</li></country><region><li>Canton de Vaud</li><li>District de Darmstadt</li><li>Hesse (Land)</li><li>Illinois</li><li>Rhénanie-Palatinat</li></region><settlement><li>Francfort-sur-le-Main</li><li>Lausanne</li><li>Mayence</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Devraj, Kavi" sort="Devraj, Kavi" uniqKey="Devraj K" first="Kavi" last="Devraj">Kavi Devraj</name></noRegion><name sortKey="Harter, Patrick N" sort="Harter, Patrick N" uniqKey="Harter P" first="Patrick N" last="Harter">Patrick N. Harter</name><name sortKey="Heilemann, Mike" sort="Heilemann, Mike" uniqKey="Heilemann M" first="Mike" last="Heilemann">Mike Heilemann</name><name sortKey="Liebner, Stefan" sort="Liebner, Stefan" uniqKey="Liebner S" first="Stefan" last="Liebner">Stefan Liebner</name><name sortKey="Mittelbronn, Michel" sort="Mittelbronn, Michel" uniqKey="Mittelbronn M" first="Michel" last="Mittelbronn">Michel Mittelbronn</name><name sortKey="Poznanovic, Slobodan" sort="Poznanovic, Slobodan" uniqKey="Poznanovic S" first="Slobodan" last="Poznanovic">Slobodan Poznanovic</name><name sortKey="Schrattenholz, Andre" sort="Schrattenholz, Andre" uniqKey="Schrattenholz A" first="André" last="Schrattenholz">André Schrattenholz</name><name sortKey="Schwall, Gerhard" sort="Schwall, Gerhard" uniqKey="Schwall G" first="Gerhard" last="Schwall">Gerhard Schwall</name><name sortKey="Spahn, Christoph" sort="Spahn, Christoph" uniqKey="Spahn C" first="Christoph" last="Spahn">Christoph Spahn</name></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Antoniello, Katia" sort="Antoniello, Katia" uniqKey="Antoniello K" first="Katia" last="Antoniello">Katia Antoniello</name></region><name sortKey="Muhs, Andreas" sort="Muhs, Andreas" uniqKey="Muhs A" first="Andreas" last="Muhs">Andreas Muhs</name><name sortKey="Paganetti, Paolo" sort="Paganetti, Paolo" uniqKey="Paganetti P" first="Paolo" last="Paganetti">Paolo Paganetti</name></country><country name="États-Unis"><region name="Illinois"><name sortKey="Hawkins, Richard A" sort="Hawkins, Richard A" uniqKey="Hawkins R" first="Richard A" last="Hawkins">Richard A. 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