Impact of platelets in the progression of Alzheimers disease

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Platelets are essential mediators of hemostasis and arterial thrombosis but also play asignificant role in inflammatory degenerative diseases such as Alzheimers disease.Alzheimers disease is characterized by deposits of neurotoxic amyloid plaques resulting in neuron loss and cognitive capability. Beside brain parenchyma, peripheral tissue is affected by the disease leading to alterations in the vascular system that induces amyloid deposits in cerebral vessels identified as cerebral Amyloidangiopathy (CAA). On the basis of vascular amyloid deposits further complications by vessel alterations and hypoperfusion play a dominant role beside the neurotoxic effects of amyloid plaques. Besides, Alzheimers disease is strongly associated with cardiovascular diseases. Substantial players in these diseases are platelets that express the Amyloid Precursor Protein (APP) and generate Amyloid beta (Abeta) peptides. In preliminary studies we were able to show that stimulation with soluble Abeta leads to adhesion, activation and aggregation of platelets in vitro und in vivo. APP23 transgenic mice (Alzheimer model mice) display a pro-thrombotic phenotype and an enhanced risk of cerebro- and cardiovascular complications. Moreover, platelets are able to modulate solubleAbeta40 resulting in fibrillar Abeta aggregation. Binding of synthetic monomeric Abeta40 to integrin alphaIIbbeta3 plays a central role in these processes and stimulates the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets both playing a crucial role in platelet-mediated Abeta aggregation. A significant reduction of vascular amyloid deposits by treatment of APP23 transgenic mice with the platelet Inhibitor Clopidogrel provided strong evidence that platelets directly contribute to CAA by promoting the formation of Abeta aggregates and that Abeta, in turn, activates platelets, creating a feed-forward loop. To date it is completely unclear, if the proteins playing a role in platelet-mediated effects of Abeta aggregation in transgenic mice, are of relevance in patients with Alzheimers disease and if anti-platelet therapy may alleviate fibril formation in cerebral vessels of these patients. The impact of platelets in the formation of parenchymal plaques as well as the consequences of Clopidogrel treatment on cognitive function of APP23 mice is likewise unknown. Therefore the aim of the project is to elucidate the role of platelets in Alzheimers disease to improve the understanding of the patho-physiological relevance of platelet-mediated cellular responses in transgenic mice and patients with Alzheimers disease. We expect to gain a new clear strategy to control platelet activity like that platelet-associated factors that account for the progression of the disease can be modulated to delay the progression of Alzheimers disease. Moreover, the analysis of platelet function might serve as a new biomarker for an early and safe diagnosis of Alzheimers disease.