Alzheimer's disease is associated with abnormalities in the vast network of blood vessels in the brain, but it hasn’t been known how this affects cognition. A study has now shown that a blood-clotting protein called fibrinogen plays a part.
The study found that fibrinogen, after leaking from the blood into the brain, activates the brain's immune cells and triggers them to destroy synapses, which are critical for neuronal communication.
Loss of synapses is known to cause memory loss, and the study found that preventing fibrinogen from activating the brain's immune cells protected Alzheimer's mice from memory loss.
Moreover, fibrinogen had this effect even in brains that lack amyloid plaques.
The findings help explain how elderly people with vascular pathology could show similar rates of cognitive decline as age-matched people with amyloid pathology. The same human studies also found that those with both types of pathology had much worse and more rapid cognitive decline.
Another study suggests that nearly half of all dementias, including Alzheimer's, begins with the breakdown of the smallest blood vessels in the brain and the "gatekeeper cells" that surround and protect the capilleries.
The collapse of pericytes (the gatekeeper cells) reduces myelin and white matter structure in the brain. They do this via fibrinogen. Fibrinogen develops blood clots so wounds can heal but when the gatekeeper cells fail, too much fibrinogen enters the brain and causes white matter to die.
Mouse studies showed that controlling fibrinogen levels can reverse or slow white matter disease.
Postmortem study of human brains found that Alzheimer’s brains had about 50% fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas, compared to healthy brains.
The mouse study found that white matter changes in mice began as early as 12 to 16 weeks old, the equivalent of 40 years in humans.
When an enzyme known to reduce fibrinogen was introduced into the mice, white matter volume returned to 90% of their normal state, and white matter connections were back to 80% productivity.
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