For release: Monday, October 4, 2010
Growing evidence points to a connection between Alzheimer’s disease and poor blood flow to the brain. Signs that a stroke has occurred are often found in the brains of Alzheimer’s patients. Meanwhile, there is evidence that stroke and Alzheimer’s disease share similar risk factors, including high blood pressure and atherosclerosis (hardening of the arteries).
A new study strengthens this connection by showing that beta-amyloid – the protein fragment that plays a defining role in Alzheimer’s – can stimulate the formation of resilient blood clots. The study also found that an anti-clotting drug (anticoagulant) had beneficial effects in a mouse model of Alzheimer’s disease.
Although used in select patients at risk for stroke, anticoagulants carry a risk of hemorrhage and are not considered an option for treating Alzheimer’s disease. But further research to identify how beta-amyloid stimulates blood clotting could lead to the development of more specific drugs that do not interfere with normal clotting, says Sidney Strickland, Ph.D., the study’s senior author and head of the laboratory of neurobiology and genetics at the Rockefeller University in New York City.
The study, published in Neuron* and funded in part by the National Institute of Neurological Disorders and Stroke, represents an evolving view of Alzheimer’s disease and the effects of beta-amyloid. Beta-amyloid accumulates in the brain tissue of people with Alzheimer’s and has a toxic effect on brain cells. Efforts to sweep beta-amyloid plaques out of the brain have been a major focus of therapy development.
However, beta-amyloid also accumulates in the blood vessels that feed the brain, a condition known as cerebral amyloid angiopathy (CAA). These beta-amyloid deposits appear to gradually cut off the brain’s blood supply, adding to the damage caused by beta-amyloid in the brain. But exactly how beta-amyloid causes a reduction in blood flow is unclear. Dr. Strickland’s team is among the first to investigate this question.
Their research points to an interaction between beta-amyloid and fibrin, a protein that forms a mesh-like structure at the core of blood clots. The team found that beta-amyloid alters the structure of this fibrin mesh, making it resistant to clot-busting enzymes in the blood. They also found that fibrin accumulates in blood vessels at the same sites as beta-amyloid. This was true in a transgenic mouse model of Alzheimer’s disease carrying a rare mutation that is associated with the disease in humans, and in postmortem tissue from Alzheimer’s patients.
To further investigate how beta-amyloid affects blood clotting, the researchers monitored cerebral blood flow in normal and transgenic mice by live imaging. They found that the transgenic mice were more prone to develop blood clots when they were exposed to damaging chemicals or to a laser beam precisely aimed at their blood vessels.
Finally, the team tested the effects of depleting fibrinogen (the precursor of fibrin) – and thus reducing the tendency to form blood clots – in the transgenic mice. In one set of experiments, they depleted fibrinogen genetically and in another, they gave the mice a month-long infusion of ancrod, a potent anticoagulant that works by inactivating fibrinogen. Both experiments reduced signs of CAA in the mice and improved their performance on spatial memory tests.
It is not yet clear if beta-amyloid and fibrinogen/fibrin interact directly, or indirectly via other proteins. Dr. Strickland and his team hope that by dissecting the interaction, they will be able to develop drugs that are capable of safely improving cerebral blood flow and staving off dementia in Alzheimer’s disease.
- By Daniel Stimson, Ph.D.
*Cortes-Canteli M, Paul J et al. Fibrinogen and beta-Amyloid association alters thrombosis and fibrinolysis: A possible contributing factor to Alzheimer's disease. Neuron, 10 June 2010, Vol. 66 (5), pp. 695-709.
Rings of beta-amyloid (red) collect along the inner walls of blood vessels in a transgenic Alzheimer’s disease mouse. The blood inside the vessels is labeled with a green fluorescent probe. Image courtesy of Neuron.
Last Modified February 1, 2013