More and more data from preclinical and clinical studies strengthen the hypothesis that immune system-mediated actions contribute to and drive pathogenesis in Alzheimer’s disease. The team of Roosmarijn Vandenbroucke in the Claude Libert Group (VIB/UGent) combined their knowledge and expertise related to inflammation with the expertise in Alzheimer’s disease present in the Bart De Strooper Group (VIB/KU Leuven). This collaboration lead to the insights that Aβ indeed induces a strong inflammatory response, thereby destroying an important but often neglected brain barrier, called the blood-cerebrospinal fluid (CSF) barrier. Disruption of this blood-CSF barrier disturbs brain homeostasis and might negatively affect disease progression. Strikingly, these effects could be blocked in the presence of a matrix metalloproteinase (MMP) inhibitor.
Roosmarijn Vandenbroucke: “Although further research is needed, these data suggest that blocking MMP activity or upstream inflammatory signalling, might have therapeutic potential to treat Alzheimer’s disease. It is important we could demonstrate the role of the blood-cerebrospinal fluid barrier, because this would be an easier target to reach in comparison with the targets of current therapies.
About this Alzheimer’s disease research
The barrier between the blood and central nervous system crumbles in Alzheimer’s disease, but researchers have known little about how this happens, or what it does to brain pathology. Two new papers shed some light on how Aβ damages the cells that protect the brain parenchyma and cerebrospinal fluid. The studies examine different systems and describe distinct mechanisms, but both add to the picture of what may happen in disease.
Source: Sooike Stoops – VIB Image Credit: The image is credited to Science Advances Original Research:Abstract for “Amyloid β Oligomers Disrupt Blood–CSF Barrier Integrity by Activating Matrix Metalloproteinases” by Marjana Brkic, Sriram Balusu, Elien Van Wonterghem, Nina Gorlé, Iryna Benilova, Anna Kremer, Inge Van Hove, Lieve Moons, Bart De Strooper, Selma Kanazir, Claude Libert, and Roosmarijn E. Vandenbroucke in Journal of Neuroscience. Published online September 15 2015 doi:10.1523/JNEUROSCI.0006-15.2015
Full open access research for “Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier” by James Keaney, Dominic M. Walsh, Tiernan O’Malley, Natalie Hudson, Darragh E. Crosbie, Teresa Loftus, Florike Sheehan, Jacqueline McDaid, Marian M. Humphries, John J. Callanan, Francesca M. Brett, Michael A. Farrell, Peter Humphries and Matthew Campbell, in Science Advances. Published online September 18 2015 doi:10.1126/sciadv.1500472
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.
SIGNIFICANCE STATEMENT 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.
“Amyloid β Oligomers Disrupt Blood–CSF Barrier Integrity by Activating Matrix Metalloproteinases” by Marjana Brkic, Sriram Balusu, Elien Van Wonterghem, Nina Gorlé, Iryna Benilova, Anna Kremer, Inge Van Hove, Lieve Moons, Bart De Strooper, Selma Kanazir, Claude Libert, and Roosmarijn E. Vandenbroucke in Journal of Neuroscience. Published online September 15 2015 doi:10.1523/JNEUROSCI.0006-15.2015
Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier
The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.
“Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier” by James Keaney, Dominic M. Walsh, Tiernan O’Malley, Natalie Hudson, Darragh E. Crosbie, Teresa Loftus, Florike Sheehan, Jacqueline McDaid, Marian M. Humphries, John J. Callanan, Francesca M. Brett, Michael A. Farrell, Peter Humphries and Matthew Campbell, in Science Advances. Published online September 18 2015 doi:10.1126/sciadv.1500472