BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.
Identifieur interne : 000171 ( PubMed/Checkpoint ); précédent : 000170; suivant : 000172BACE-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><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">26661166</PMID><DateCreated><Year>2016</Year><Month>07</Month><Day>01</Day></DateCreated><DateRevised><Year>2016</Year><Month>07</Month><Day>14</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1559-7016</ISSN><JournalIssue CitedMedium="Internet"><Volume>36</Volume><Issue>7</Issue><PubDate><Year>2016</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism</Title><ISOAbbreviation>J. Cereb. Blood Flow Metab.</ISOAbbreviation></Journal><ArticleTitle>BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease.</ArticleTitle><Pagination><MedlinePgn>1281-94</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1177/0271678X15606463</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© The Author(s) 2015.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Devraj</LastName><ForeName>Kavi</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany drivak@yahoo.com stefan.liebner@kgu.de.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Poznanovic</LastName><ForeName>Slobodan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Orgentec GmbH, Mainz, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spahn</LastName><ForeName>Christoph</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schwall</LastName><ForeName>Gerhard</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Orgentec GmbH, Mainz, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Harter</LastName><ForeName>Patrick N</ForeName><Initials>PN</Initials><AffiliationInfo><Affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mittelbronn</LastName><ForeName>Michel</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Antoniello</LastName><ForeName>Katia</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Paganetti</LastName><ForeName>Paolo</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Muhs</LastName><ForeName>Andreas</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>AC Immune SA, PSE-B EPFL, Lausanne, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Heilemann</LastName><ForeName>Mike</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hawkins</LastName><ForeName>Richard A</ForeName><Initials>RA</Initials><AffiliationInfo><Affiliation>Dept of Physiology/Biophysics, University of Health Sci./Chicago Medical School, Illinois, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schrattenholz</LastName><ForeName>André</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Pivot GmbH, Trier, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liebner</LastName><ForeName>Stefan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Edinger Institute of Neurology, Goethe University Medical School, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>10</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Cereb Blood Flow Metab</MedlineTA><NlmUniqueID>8112566</NlmUniqueID><ISSNLinking>0271-678X</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><OtherID Source="NLM">PMC4929696 [Available on 07/01/17]</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Alzheimer’s disease</Keyword><Keyword MajorTopicYN="N">BACE-1</Keyword><Keyword MajorTopicYN="N">blood–brain barrier</Keyword><Keyword MajorTopicYN="N">endothelium</Keyword><Keyword MajorTopicYN="N">β-amyloid</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>01</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>07</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="pmc-release"><Year>2017</Year><Month>07</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26661166</ArticleId><ArticleId IdType="pii">0271678X15606463</ArticleId><ArticleId IdType="doi">10.1177/0271678X15606463</ArticleId><ArticleId IdType="pmc">PMC4929696</ArticleId></ArticleIdList></PubmedData></pubmed><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. Hawkins</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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