Blood Protein May Offer New Approaches to Alzheimer’s Disease Therapy

Thrombin is well known for its role in blood clotting and other inflammatory response processes. New evidence from the Ryan Institute suggests it may be a good target for therapies to head off Alzheimer’s disease.

Images of brain tissue from control mice (C), control mice treated with the direct thrombin inhibitor dabigatran (DTI), mice with an Alzheimer’s-like disease (AD) and AD mice treated with DTI. Tissue was marked with fluorescent antibodies against hypoxia-inducible factor 1α (HIF-1α, green), an indication of inflammation, and Von Willebrand factor (VWF, red), a marker for endothelial cells. Note that HIF-1α fluorescence is markedly lower in AD+DTI tissue compared to untreated AD, an indication that inhibiting thrombin has reduced the inflammatory activation of endothelial cells.

Images of brain tissue from control mice (C), control mice treated with the direct thrombin inhibitor dabigatran (C+DTI), mice with an Alzheimer’s-like disease (AD) and AD mice treated with DTI. Tissue was labeled with fluorescent antibodies against hypoxia-inducible factor 1α (HIF-1α, green), an indication of inflammation, and von Willebrand factor (vWF, red), a marker for endothelial cells. Note that HIF-1α fluorescence is markedly lower in AD+DTI tissue compared to untreated AD, an indication that inhibiting thrombin has reduced the inflammatory activation of endothelial cells.

Previous work in the lab of Executive Director Paula Grammas showed that blocking inflammatory processes in blood vessels in the brain improved cognitive performance in mice which develop an Alzheimer’s-like disease. The compounds used in those studies are not suitable for clinical trials in human Alzheimer’s disease patients, however. Thrombin, on the other hand, is the target of several FDA-approved medications that inhibit its function. It’s also one of the first proteins released during the inflammatory process; these two factors made it a promising subject for new studies.

In a presentation at the 2017 Clinical Trials on Alzheimer’s Disease conference, Grammas presented early evidence that inhibiting thrombin with the drug dabigatran reduces the production of other inflammatory proteins, affecting the biochemical pathways previously linked to neurodegeneration. The effect was observed in two different systems: when inflammatory responses were provoked by reducing the oxygen available to isolated brain-blood-vessel cells in culture, and when dabigatran was given to Alzheimer’s-like mice.

These new observations extend the connection between blood brain vessels and Alzheimer’s disease and highlights its potential as an innovative route to treating Alzheimer’s disease and dementia.