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DOI: 10.1055/s-0041-1728208
The role of platelet mitochondrial function for platelet mediated Aβ40 aggregation
Objective Alzheimer’s disease (AD) is a neurodegenerative disease with Aβ deposits in the brain parenchyma and in the walls of cerebral blood vessels, strongly associated with Reactive Oxygen Species (ROS) production and oxidative stress. Mitochondrial abnormalities act as major producers of ROS. Recently, we have shown that platelets directly contribute to the formation of Aβ fibrils in vitro and in vivo, including integrin outside-in and ADP-P2Y12 signaling. However, the role of mitochondrial damage for platelet-mediated Aβ fibril formation is completely unknown
Material and Methods Cell culture experiments, flow chamber experiments and FACS analysis.
Results Defects in the respiratory chain by treatment of platelets with Antimycin A (inhibition of mitochondrial complex III) and Rotenone (inhibition of mitochondrial complex I) in the presence of soluble Aβ40 increased Aβ fibril formation in a dose-dependent manner in vitro. However, the addition of the antioxidant vitamin C prevents platelet mediated Aβ40 fibril formation suggesting increased ROS production upon mitochondrial complex inhibition. In contrast, blocking of mitochondrial complex I in platelets reduced Aβ40-mediated aggregation and ATP release of platelets. In addition, incubation of platelets with Aβ40 enhances the generation of ROS and superoxide, which leads to the reduction of the mitochondrial membrane potential in platelets. Moreover, the mitochondrial membrane potential of platelets from the AD transgenic APP23 mouse was reduced already under resting conditions, as well as upon Aβ40 and GPVI stimulation compared to controls. Accordingly, superoxide generation was enhanced in platelets from APP23 mice in the presence of Aβ40
Conclusion Platelet mitochondrial dysfunction contributes to platelet mediated Aβ fibril formation.
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Publikationsverlauf
Artikel online veröffentlicht:
18. Juni 2021
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