Oral treatment over one year with an approved blood thinner called dabigatran prevented memory loss, preserved blood circulation in the brain and reduced the amount of senile plaques in a mouse model of Alzheimer’s disease.
The study with that finding, “Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model,” was published in the Journal of the American College of Cardiology.
Previous studies have shown a link between vascular disease and Alzheimer’s development. Reduced blood circulation leads to an insufficient supply of nutrients and oxygen to nerve cells, causing cell death.
Researchers at Centro Nacional de Investigaciones Cardiovasculares (CNIC), in Spain, and at The Rockefeller University, in New York, evaluated whether dabigatran (sold under the brand name Pradaxa among others) could improve blood circulation and delay Alzheimer’s progression.
Dabigatran is an effective oral anticoagulant, or blood thinner. It is approved for several indications, including prevention of stroke in patients with an abnormal heartbeat (nonvascular atrial fibrillation) and venous thromboembolism, a condition that arises when a blood clot (thrombus) forms in a vein. Dabigatran has a low risk for brain bleeding and also is a powerful anti-inflammatory agent.
To test its potential benefits, researchers used the TgCRND8 mouse model of Alzheimer’s. Mice were treated with dabigatran (5 mg per gram of food) or a placebo from 2 months of age for 6 months or one year. Of note, in this mouse model, beta-amyloid protein aggregates — the main component of senile plaques — are detected soon after two months of age.
To assess behavior, researchers used a test called Barnes maze. This test assesses spatial learning and memory, both controlled by the hippocampus, one of the first regions of the brain showing alterations in people with Alzheimer’s.
Results showed that, after one year of treatment, dabigatran prevented decline in spatial memory when compared to placebo in mice with Alzheimer’s. Also, after receiving dabigatran, these mice showed a performance in the Barnes maze comparable to control animals without the disease.
Analysis of brain tissue revealed that long-term dabigatran reduced the levels of beta-amyloid plaques by 23.7% compared to animals given placebo. Signs of neuroinflammation also were decreased, as shown by a more than 30% reduction in immune T-cells infiltrates.
Dabigatran also prevented the accumulation of fibrin. This protein accumulates in the brain of people with Alzheimer’s due to the damage in the blood-brain barrier, a semi-permeable barrier that separates the brain from the circulatory system.
In fact, the team found that dabigatran helped maintain the integrity and function of the barrier, as assessed by the levels and localization of the water channel aquaporin 4. That protein has several functions, including controlling the flux of water between the blood and brain and regulating cerebrospinal fluid circulation (that which surrounds the brain and spinal cord).
Compared to placebo, dabigatran further prevented the decreased blood circulation in the brain, suggesting that its therapeutic benefits in Alzheimer’s result from normalizing blood flow to the brain.
“Winning the battle against Alzheimer’s disease will require individualized combination therapy targeting the various processes that contribute to this disease,” Marta Cortés-Canteli, a CNIC researcher and the study’s first author, said in a press release.
“One goal is to improve the cerebral circulation, and our study shows that treatment with oral anticoagulants has the potential to be an effective approach in Alzheimer’s patients with a tendency to coagulation,” she said.
Studies on patients are now needed to understand how beneficial this therapy can be. But Cortés-Canteli cautioned that, before establishing blood thinners as a new treatment strategy in Alzheimer’s, researchers still need to develop a diagnostic tool to identify patients prone to coagulation. “This will be an important line of research in the coming years,” she commented.
Valentín Fuster, CNIC general director and the study’s lead author, added a broader context: “Neurodegenerative diseases are very closely linked to disease in the cerebral blood vessels. The study of the links between the brain and heart is the major challenge for the next ten years.”
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