New research from the University of Southern California has shed light on how the decline of the brain’s vascular system precedes the build-up of the plaques and tau tangles associated with Alzheimer’s disease.
A leaky blood-brain barrier sets the scene for dementia
Traditionally, many researchers have focused their efforts on the amyloid and tau proteins that accumulate in the brain and are typical of Alzheimer’s disease progression. However, the researchers in this new study suggest that the problem begins before this due to a leaking blood-brain barrier .
The brain is isolated from the rest of the body to a greater extent thanks to a protective membrane known as the blood-brain barrier, which is made from specialized cells that form a sheath that surrounds the blood vessels in the brain and keeps out most molecules circulating in the bloodstream.
The brain is significantly different from the rest of the body, and many molecules that are commonly found elsewhere in the body are harmful to the brain, so an intact barrier is necessary for brain health.
The blood-brain barrier is populated by cells known as pericytes that become dysfunctional and collapse as we age. This leads to the loss of blood-brain barrier integrity, allowing unwanted molecules to enter the brain. This leakage sets the scene for white matter disease and dementia.
According to the study, one of those unwanted molecules entering the brain is fibrinogen, a circulating protein in the bloodstream that helps blood clots to form allowing wounds to heal. When pericytes collapse, fibrinogen infiltrates the blood-brain barrier and starts to destroy white matter, axons, and oligodendrocytes.
In the study, the researchers showed that in autopsies of human brains with Alzheimer’s there were significantly increased levels of fibrinogen, in particular in the damaged areas of the brain. This shows that the blood-brain barrier is compromised and confirms what they also observed in the brains of mice.
Confirming that fibrinogen proteins are harmful to the brain
To show that fibrinogen is harmful when present in the brain; they used a type of enzyme that reduces fibrinogen in the bloodstreams and brains of mice. The mice treated with this enzyme had their white matter restored to 90 percent of its original volume, and white matter connections saw an 80 percent improvement.
The researchers conclude that this demonstrates that targeting fibrinogen and reducing its levels in the brain can slow or even reverse white matter disease. Unfortunately, it isn’t viable to remove fibrinogen from the bloodstream, as it is critical for wound healing; it’s just a problem if it reaches the brain. They suggest that perhaps a possible way forward would be to focus on strengthening the integrity of the blood-brain barrier in order to prevent fibrinogen from entering the brain.
It is good to see researchers exploring other avenues and targets for combating dementia, especially ones that are tracing the process back to where pathology begins instead of attempting to treat the consequences. The fact that they are talking about improving the integrity of the blood-brain barrier seems to be a move in a positive direction, especially if they correctly conclude that the aging processes are why it fails in the first place and target those process directly.
 Axel Montagne, Angeliki M Nikolakopoulou, Zhen Zhao, Abhay P Sagare, Gabriel Si, Divna Lazic, Samuel R Barnes, Madelaine Daianu, Anita Ramanathan, Ariel Go, Erica J Lawson, Yaoming Wang, William J Mack, Paul M Thompson, Julie A Schneider, Jobin Varkey, Ralf Langen, Eric Mullins, Russell E Jacobs & Berislav V Zlokovic (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nature Medicine doi:10.1038/nm.4482.