Amyloid plaques (red) infiltrate neurons in this thin section of brain taken from a person who had Alzheimer's disease in his or her lifetime. | James Keaney
Two proteins that regulate a tight fit between blood vessel cells could offer new targets for treating damaging protein buildup in Alzheimer's disease, according to a new report in the open-access journal Science Advances.
The research published 18 September is one of the first descriptions of how protein fragments called amyloid-beta can slip out of the brain through the space between cells. In Alzheimer's disease, amyloid-beta clumps together into larger protein plaques that are toxic to nerve cells.
To learn more about why these clumps occur, Matthew Campbell, a genetics and microbiology assistant professor at Trinity College Dublin and his colleagues took a closer look at the blood-brain barrier. This unique filtering system in the small blood vessels threaded through the brain keeps out chemical toxins and microbes while allowing other molecules — such as amyloid-beta — to move out of the brain into the bloodstream.
Tight junctions between endothelial cells form part of the blood-brain barrier that becomes dysfunctional in Alzheimer's disease.| James Keaney
The barrier works in part due to a tight fit between the endothelial cells that line these blood vessels, a fit that is regulated by the proteins claudin-5 and occludin. When levels of these two proteins temporarily fall off, Campbell's team discovered, the tight junctions between cells slacken enough to allow amyloid-beta to slip between cells and out of the brain. Amyloid-beta itself appears to lower the levels of these two proteins to give itself this escape route, the researchers said.
But this pathway out of the brain seems to be closed in people with Alzheimer's disease, the researchers note. When Campbell and colleagues looked at brain tissue from the Dublin Brain Bank from people who had died with Alzheimer's disease, they found that brains with high levels of amyloid-beta and a large number of blood vessels choked with amyloid plaques also had surprisingly low levels of claudin-5 and occludin.
Amyloid-beta could be adjusting the levels of occludin and claudin-5 in these Alzheimer's brains, Campbell and colleagues suggest, but the plaques formed by amyloids are too large to fit through the gaps between the cells. Instead, the plaques accumulate and overwhelm the brain's nerve cells and blood vessels.
The researchers injected small interfering RNA molecules (siRNA) into mice engineered to have high levels of amyloid-beta in their brains, using the siRNA to knock down the levels of occludin and claudin-5 in the mice. When both proteins were blocked in this way, the mice had less amyloid-beta in their brains and more amyloid in their blood than at the start of the experiments, and their performance on cognition tests improved as well.
These results indicate that occludin and claudin-5 might be useful treatment targets for Alzheimer's disease in the future, said Campbell. He cautioned, however, that scientists need to know more about what might happen in humans when the blood-brain barrier is breached by adjusting these proteins.
"Ideally, our approach would be paired with the current development of antibodies against amyloid-beta, as the antibodies would 'draw' the amyloid-beta from brain to blood between the endothelial cells," Campbell said. "While it's very early days, it's definitely worth considering if this could be a novel means of therapeutically addressing Alzheimer's disease."