A research team from Nanjing, China has discovered neuroprotective effects from catalpol, a root extract which has previously been shown to have anti-oxidative properties.
The group created a blood-brain barrier in the lab and used amyloid-beta peptide to induce damage before treating the cells with catalpol. They established that catalpol protects brain endothelial cells from amyloid-beta peptide induced damage through a range of proteins which clear amyloid from the brain.
In Alzheimer’s disease, amyloid-beta peptides form a major pathological hallmark, aggregating in the brain and cause neurodegeneration through multiple pathways.
One of these neurodegenerative pathways is through damage to the brain blood vessels, which are crucial to supplying the brain with oxygen through blood flow and clearing potentially damaging substances from the brain. This forms part of a ‘dual hit’ hypothesis where neurovascular dysfunction either instigates or exacerbates the build-up of amyloid plaques and other Alzheimer’s hallmarks from the brain.
Endothelial Cells And Astrocytes
The group developed their blood-brain barrier model in the lab using mouse brain endothelial cells and astrocytes, separated by semi-permeable plastic membrane. The addition of astrocytes to the model was to further functionalise the brain endothelial cells to behave more like those in a living blood-brain barrier.
Astrocytes are brain specific cells that have been shown previously to interact with brain blood vessels to increase tight junctions – which bind endothelial cells and stop foreign entities entering the brain – as well as increasing neurovascular coupling.
After dosing the cells with amyloid-beta peptide, researchers measured dysfunctional levels of protein responsible for transport of amyloid-beta peptide, increased levels of potentially damaging matrix metlloproteinases, and reduced levels of tight junctions, which ensure the blood-brain barrier remains intact.
By treating with catalpol, the researchers established rescue of all of the dysfunctional processes described above, as well as a reduced level of leakage of amyloid-beta peptide through the blood-brain barrier. In addition, catalpol inhibited cell death through death receptor and mitochondria dependent pathways.
This indicates that catalpol works at the brain blood vessels to increase vascular integrity through multiple cellular molecules and proteins.
The research findings from this study reinforce previous evidence that amyloid-beta peptides damage brain endothelial cells and the processes crucial to clearance of amyloid-beta peptides. This vascular damage could contribute to Alzheimer’s disease related pathology through the reduced clearance of amyloid peptides, but also through the infiltration of foreign components to the brain which can lead to a damaging inflammatory response, progressing neurodegeneration.
This study indicates that catalpol could be used to treat Alzheimer’s disease to reinforce the blood-brain barrier. This could be put into effect either by itself or in conjunction with other disease mediating drugs to treat the other pathological hallmarks of Alzheimer’s disease.
The authors do present these results with caution, stating that for catalpol to truly be considered as a potential Alzheiemer’s disease modifying therapeutic, these results will need to be confirmed in animal models.
Catalpol effects aside, this study’s findings of amyloid-beta peptides effects on brain endothelial cells are interesting and reinforce the notion that neurovascular unit dysfunction forms a major aspect of Alzheimer’s disease pathology. The replication of these results in a disease relevant cell type or a more physiologically relevant model would be needed to further strengthen these findings.
The brain endothelial cell type used is of mouse origin, and advances in stem cell technologies could enable the replication of this study with human cells as well as Alzheimer’s disease patient cells.
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Image: Shizhao CC BY 2.5, via Wikimedia Commons. Rehmannia glutinosa, from which catapol is extracted.