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Vicious circle of platelets: Alzheimer's disease patients may benefit from anti-platelet therapy

May 31, 2016

Inhibition of platelets in Alzheimer's disease patients may become an important in therapy in future. Research findings of an international research team led by Professor Margitta Elvers, Institute of Hemostasis, Hemotherapy and Transfusion Medicine, University Clinic Düsseldorf, Germany, could be of great importance for the treatment of Alzheimer's disease patients.

They were published in the current issue of the renowned journal Science Signaling. The scientists provide evidence for the first time that treatment of Alzheimer transgenic model mice with an anti-platelet drug leads to significantly reduced amyloid plaques in cerebral vessels. They together with scientists from the Research Center Jülich, Germany, identified a key mechanism for a direct involvement of platelets in the progression of the disease.

Alzheimer's disease is an age-related neurodegenerative disorder that is the most common form of senile dementia with about 35 million people worldwide who are affected by this progressive cognitive decline. By 2030, the number of Alzheimer's disease patients is predicted to increase to > 66 million people; by 2050 the number is predicted to increase already to 115 million people. Alzheimer's disease is characterized by the formation of protein agglutination, so called amyloid aggregates, and deposits of amyloid in the brain. These amyloid deposits damage structure and function of nerve tissue in the brain and lead to the loss of neuronal cells and cognitive capability.

Formation of amyloid deposits in Alzheimer's disease patients occurs not only in brain parenchyma but also in blood vessels in the brain that contributes to the severity of Alzheimer's disease pathology. The scientists from Düsseldorf already demonstrated that attachment of platelets to amyloid deposits of the vessel wall leads to ongoing platelet activation in mice. Platelets stick together and form a hemostatic plug which induced the occlusion of vessels in the brain leading to insufficient perfusion of the surrounding tissue. The current published results are predicted on the vascular form of the disease.

An involvement of platelets in Alzheimer's disease is assumed for many years. The scientists from Düsseldorf and Jülich were now able to identify the key mechanisms of a direct involvement of platelets. This mechanism is characterized by the binding of the protein amyloid-? to a specific integrin, a receptor on the platelet surface that is important for the aggregation of platelets. This binding induces the release of adenosine diphosphate (ADP) and clusterin and supports the formation of amyloid plaques. Platelets from patients with Glanzmann's thrombasthenia, a hereditary defect of platelet activation, showed no amyloid plaques in cell culture experiments.

Anti-platelet agents such as Clopidogrel are applied for the therapy and prevention of blood clots that provoke myocardial infarction and stroke. Treatment of Alzheimer transgenic mice with Clopidogrel led to reduced platelet activation, significantly reduced amyloid plaque formation and thus improved the perfusion of the brain when these mice were treated with the anti-platelet drug for three months. "Platelets directly influence the formation of amyloid deposits in cerebral vessels, and A?, in turn, activates platelets, creating a feed-forward loop that supports fibril formation in cerebral vessels of Alzheimer's disease patients" says Margitta Elvers.

If platelets have an impact on the formation of amyloid plaques in brain tissue will be investigated by the scientists of Düsseldorf University at present.
Original publication:

Science Signaling, Donner et al., 2016, Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ33-induced outside-in signaling and clusterin release

Heinrich-Heine University Duesseldorf

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