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Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases

(2015) JOURNAL OF NEUROSCIENCE. 35(37). p.12766-12778
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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 beta (A beta) 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 A beta on the functionality of the BCSFB. Intracerebroventricular injection of A beta 1-42 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. A beta 1-42 oligomers also increased matrix metalloproteinase (MMP) gene expression in the CPE and its activity in CSF. Interestingly, BCSFB disruption induced by A beta 1-42 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 A beta 1-42 oligomers. Our results reveal that Alzheimer's disease-associated soluble A beta 1-42 oligomers induce BCSFB dysfunction and suggest MMPs as a possible therapeutic target.
Keywords
ONSET ALZHEIMERS-DISEASE, PERIPHERAL INFLAMMATORY STIMULUS, matrix metalloproteinases, choroid plexus, blood-CSF barrier, amyloid beta toxicity, Alzheimer's disease, CHOROID-PLEXUS RESPONSE, SPINAL-CORD-INJURY, CEREBROSPINAL-FLUID, BRAIN-BARRIER, PEPTIDE 1-42, IN-VITRO, PROTEIN, EXPRESSION

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Citation

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Chicago
Brkić, Marjana, Sriram Balusu, Elien Van Wonterghem, Nina Gorlé, Iryna Benilova, Anna Kremer, Inge Van Hove, et al. 2015. “Amyloid β Oligomers Disrupt blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases.” Journal of Neuroscience 35 (37): 12766–12778.
APA
Brkić, M., Balusu, S., Van Wonterghem, E., Gorlé, N., Benilova, I., Kremer, A., Van Hove, I., et al. (2015). Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases. JOURNAL OF NEUROSCIENCE, 35(37), 12766–12778.
Vancouver
1.
Brkić M, Balusu S, Van Wonterghem E, Gorlé N, Benilova I, Kremer A, et al. Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases. JOURNAL OF NEUROSCIENCE. 2015;35(37):12766–78.
MLA
Brkić, Marjana, Sriram Balusu, Elien Van Wonterghem, et al. “Amyloid β Oligomers Disrupt blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases.” JOURNAL OF NEUROSCIENCE 35.37 (2015): 12766–12778. Print.
@article{6987629,
  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 beta (A beta) 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 A beta on the functionality of the BCSFB. Intracerebroventricular injection of A beta 1-42 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. A beta 1-42 oligomers also increased matrix metalloproteinase (MMP) gene expression in the CPE and its activity in CSF. Interestingly, BCSFB disruption induced by A beta 1-42 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 A beta 1-42 oligomers. Our results reveal that Alzheimer's disease-associated soluble A beta 1-42 oligomers induce BCSFB dysfunction and suggest MMPs as a possible therapeutic target.},
  author       = {Brki\'{c}, Marjana and Balusu, Sriram and Van Wonterghem, Elien and Gorl{\'e}, Nina and Benilova, Iryna and Kremer, Anna and Van Hove, Inge and Moons, Lieve and De Strooper, Bart and Kanazir, Selma and Libert, Claude and Vandenbroucke, Roosmarijn},
  issn         = {0270-6474},
  journal      = {JOURNAL OF NEUROSCIENCE},
  language     = {eng},
  number       = {37},
  pages        = {12766--12778},
  title        = {Amyloid \ensuremath{\beta} oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0006-15.2015},
  volume       = {35},
  year         = {2015},
}

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