Inhibition of platelets in Alzheimer’s disease patients may become important in therapy in the future, say researchers. The findings were published in the current issue of the renowned journal “Science Signaling”. The team lead by scientists from the University Clinic Düsseldorf for the first time provides evidence that the treatment of Alzheimer transgenic model mice with an anti-platelet drug leads to a significant reduction in amyloid plaques in cerebral vessels. Together with scientists at Heinrich-Heine-University Düsseldorf and Forschungszentrum Jülich, Germany, they 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 characterized by a progressive cognitive decline. It is the most common form of senile dementia, affecting about 35 million people worldwide. By the year 2030, the number of Alzheimer’s disease patients is predicted to increase to more that 66 million people and to to 115 million people by 2050. Alzheimer’s disease is characterized by the clumping of the endogenous protein amyloid-β, leading to the formation of so called amyloid aggregates and deposits of amyloid in the brain. These amyloid aggregates and 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 the blood vessels of the brain, contributing to the severity of Alzheimer’s disease pathology. The scientists from Düsseldorf had previously 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 relate to the vascular form of the disease.
An involvement of platelets in Alzheimer’s disease has been assumed for many years. The scientists, together with colleagues from Heinrich-Heine-University Düsseldorf and the Institute of Complex Systems: Structural Biochemistry (ICS-6) at Forschungszentrum Jülich were now able to identify a key mechanism for the direct involvement of platelets. This mechanism is characterized by the binding of the protein amyloid-β to a specific integrin, a receptor on the platelet surface that is important for platelet aggregation. 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 drugs 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 and a significantly reduced amyloid plaque formation, thus improving 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 Aβ, in turn, activates platelets, creating a feed-forward loop that supports fibril formation in cerebral vessels of Alzheimer’s disease patients” says Margitta Elvers from University Clinic Düsseldorf, who lead the study.
Whether platelets have an impact on the formation of amyloid plaques in brain tissue is currently being investigated.
Science Signaling, Donner et al., 2016, Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3–induced outside-in signaling and clusterin release