title: Amyloid β Oligomers Disrupt Blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases.
abstract: The blood-CSF barrier (BCSFB) consists of a monolayer of choroid plexus epithelial (CPE) cells that maintain CNS homeostasis by producing CSF and restricting the passage of undesirable molecules and pathogens into the brain. Alzheimer's disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles in the brain. Recent research shows that Alzheimer's disease is associated with morphological changes in CPE cells and compromised production of CSF. Here, we studied the direct effects of Aβ on the functionality of the BCSFB. Intracerebroventricular injection of Aβ1-42 oligomers into the cerebral ventricles of mice, a validated Alzheimer's disease model, caused induction of a cascade of detrimental events, including increased inflammatory gene expression in CPE cells and increased levels of proinflammatory cytokines and chemokines in the CSF. It also rapidly affected CPE cell morphology and tight junction protein levels. These changes were associated with loss of BCSFB integrity, as shown by an increase in BCSFB leakage. Aβ1-42 oligomers also increased matrix metalloproteinase (MMP) gene expression in the CPE and its activity in CSF. Interestingly, BCSFB disruption induced by Aβ1-42 oligomers did not occur in the presence of a broad-spectrum MMP inhibitor or in MMP3-deficient mice. These data provide evidence that MMPs are essential for the BCSFB leakage induced by Aβ1-42 oligomers. Our results reveal that Alzheimer's disease-associated soluble Aβ1-42 oligomers induce BCSFB dysfunction and suggest MMPs as a possible therapeutic target.
  
  
  CONCLUSIONS
  No treatments are yet available to cure Alzheimer's disease; however, soluble Aβ oligomers are believed to play a crucial role in the neuroinflammation that is observed in this disease. Here, we studied the effect of Aβ oligomers on the often neglected barrier between blood and brain, called the blood-CSF barrier (BCSFB). This BCSFB is formed by the choroid plexus epithelial cells and is important in maintaining brain homeostasis. We observed Aβ oligomer-induced changes in morphology and loss of BCSFB integrity that might play a role in Alzheimer's disease progression. Strikingly, both inhibition of matrix metalloproteinase (MMP) activity and MMP3 deficiency could protect against the detrimental effects of Aβ oligomer. Clearly, our results suggest that MMP inhibition might have therapeutic potential.
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium, Department of Neurobiology, Institute for Biological Research, University of Belgrade, 11060 Belgrade, Republic of Serbia, and.
authors.forename: Marjana
authors.initials: M
authors.lastname: Brkic
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Sriram
authors.identifier: http://orcid.org/0000-0003-1424-0577
authors.initials: S
authors.lastname: Balusu
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Van Wonterghem
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: Gorlé
authors.affiliation: Center for the Biology of Disease, VIB, B-3000 Leuven, Belgium, Center for Human Genetics and Leuven Institute of Neuroscience and Disease, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kremer
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Van Hove
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.affiliation: Center for the Biology of Disease, VIB, B-3000 Leuven, Belgium, Center for Human Genetics and Leuven Institute of Neuroscience and Disease, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.affiliation: Department of Neurobiology, Institute for Biological Research, University of Belgrade, 11060 Belgrade, Republic of Serbia, and.
authors.forename: Selma
authors.initials: S
authors.lastname: Kanazir
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Inflammation Research Center, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium, Roosmarijn.Vandenbroucke@irc.VIB-UGent.be.
authors.forename: Roosmarijn E
authors.identifier: http://orcid.org/0000-0002-8327-620X
authors.initials: RE
authors.lastname: Vandenbroucke
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001704:Biopolymers; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology; D002199:Capillary Permeability / Q000187:drug effects; D048430:Cell Shape; D018925:Chemokines / Q000134:cerebrospinal fluid; D002831:Choroid Plexus / Q000166:cytology; D016207:Cytokines / Q000134:cerebrospinal fluid; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D007276:Injections, Intraventricular; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D001704:Biopolymers; D018925:Chemokines; D016207:Cytokines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011480:Protease Inhibitors; C075222:amyloid beta-protein (1-42); D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse
keywords: Alzheimer's disease; amyloid β toxicity; blood–CSF barrier; choroid plexus; matrix metalloproteinases