A New Culprit in Cognitive Decline

Fibrinogen (red), amyloid (blue), and damaged neuronal projections (green) in the Alzheimer's disease mouse brain.

Mario Merlini, Akassoglou Lab

According to the U. S. Centers for Disease Control and Prevention, close to five million Americans live with Alzheimer’s disease. Current Alzheimer’s research largely focuses on targeting the build-up of amyloid plaques, bunches of proteins found in the brains of people with Alzheimer’s and other neurodegenerative diseases. A recent study investigates another culprit that can also cause cognitive impairment: a blood plasma protein called fibrinogen, which can enter the brain when blood leaks through the blood-brain barrier.

Scientists from the Gladstone Institutes, a nonprofit medical research organization affiliated with the University of California at San Francisco, examined how blood leakage can cause cognitive issues, such as memory loss. In brain images of mouse models of Alzheimer’s disease and of humans with Alzheimer’s disease, the Gladstone scientists found that areas of the brain containing fibrinogen also had fewer dendritic spines, a crucial component of neurons that allow them to communicate. Such disrupted neural connections could account for the memory loss.

Based on earlier research, the researchers knew that fibrinogen can bind to amyloids, making it more difficult for fibrinogen to break down and exit the brain. Thus, they hypothesized that something about bonded fibrinogen and amyloids caused cognitive decline. Their images, however, showed that areas of the brain with fibrinogen—but no amyloid build-ups—still had compromised neural connections, which suggests that fibrinogen can trigger cognitive decline on its own. To test this hypothesis, researchers injected fibrinogen into the brains of mice with no amyloid plaques. Imaging three days after injection showed significant drops in dendrites and dendritic spines following fibrinogen injection, in the absence of amyloid.

Finally, the researchers linked the negative effects of fibrinogen to CD11b, a receptor that activates the brain’s immune response. Blocking CD11b prevented dendrite and dendritic spine loss following fibrinogen injection. When the researchers genetically engineered an Alzheimer’s disease mouse model to produce fibrinogen without the CD11b binding site, the resulting diseased mice with altered fibrinogen still showed amyloid plaques (though fewer than did the unaltered Alzheimer’s disease mice). They did not, however, show the learning and memory deficits found in the unaltered Alzheimer’s disease mice.

Says lead author Katerina Akassaglou, “For the first time, we have a pathway we can potentially target. Now we know that when blood leaks in the brain, that can be toxic to neurons.” (Neuron)