Toska, L. M. | Search bioRxiv

bioRxiv2025

Long-term antiplatelet therapy protects against cerebral but not parenchymal amyloid plaque formation and neurodegeneration in transgenic mice of Alzheimers disease

IntroductionCerebral amyloid angiopathy (CAA) is characterized by the aggregation of amyloid-{beta} peptides in cerebral blood vessels, leading to a loss of vascular integrity and contributing to the progression of Alzheimers disease (AD). In our previous study, we showed that short-term treatment with the antiplatelet drug clopidogrel, a P2Y12 inhibitor that irreversibly blocks ADP signaling, reduced the incidence of CAA in the APP23 mouse model of Alzheimers disease providing strong evidence for platelets to contribute to AD pathology. The objective of the present study was to ascertain whether long-term treatment with clopidogrel and the earlier initiation of treatment prior to the formation of A{beta} deposits prevents pathological changes associated with Alzheimers disease. MethodsAPP23 mice were treated with clopidogrel for 15 month and analyzed for AD pathology. ResultsWe detected increased permeability of the blood brain barrier in different brains regions of APP23 mice. Moreover, platelets migrated into the brain parenchyma and accumulated around amyloid plaques in the brain of APP23 mice. Although we detected platelets in close proximity to microglia and neurons in the cortex and hippocampus of APP23 mice, we did not observe any differences in neurodegeneration or gliosis in Clopidogrel treated APP23 mice. Furthermore, pathological analysis showed a significant reduction in CAA and in soluble A{beta}42 levels in the brain of Clopidogrel versus placebo treated APP23 mice but no differences in plaque load in the brain parenchyma. ConclusionThus, antiplatelet therapy may alleviate amyloid pathology in cerebral vessels leading to improved blood perfusion in AD patients.

pathology↗

bioRxiv2022

Platelet pannexin-1 channels modulate inflammation during abdominal aortic aneurysm formation

Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in AAA formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP)VI. Since platelets play a role in cardiovascular diseases including AAA, we analyzed the contribution of platelet Panx1 in the progression of AAA. We detected enhanced Panx1 plasma levels in AAA patients. In experimental AAA using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect AAA formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in AAA via Panx1 channels and adds important knowledge about the significance of platelets in AAA pathology important for the establishment of an anti-platelet therapy for AAA patients.

cell biology↗