Abstract We0028: Effects of Amyloid Beta Peptides on Procoagulant Platelet Generation

Background: Alzheimer’s disease (AD) is a cerebrovascular disorder marked by fibrillar amyloid beta (Aβ) plaques in the cerebral microvasculature, leading to neurodegeneration and dementia. Blood platelets are key sources of amyloid precursor protein (APP) and Aβ peptides. Severe cognitive decline in AD patients is often linked to high procoagulant platelet activity. However, the connection between Aβ peptides and procoagulant platelet generation, as well as the platelet-driven processes behind amyloid fibril formation, remains unclear. Results: Exposure to both Aβ 1-40 and Aβ 1-42 resulted in a noticeable increase in platelet aggregation, with Aβ 1-42 having a significantly greater effect than Aβ 1-40 . Flow cytometry further demonstrated that platelets stimulated by Aβ 1-42 exhibited a marked increase in granule secretion (e.g., P-selectin expression) and activation of integrin αIIbβ3, emphasizing the stronger influence of Aβ 1-42 on platelet activation. Using lactadherin-FITC to label extracellular phosphatidylserine (PS) exposure, we observed that Aβ 1-42 transformed the majority of platelets into a procoagulant state. In live cell imaging experiments, co-localization of procoagulant platelets stimulated by Aβ 1-42 and amyloid fibrils was visualized using Annexin V staining for PS and Amytracker staining for amyloid fibril formation. In contrast, such co-localization was not detected with Aβ 1-40 . Additionally, treatment with the BTK inhibitor ibrutinib selectively inhibited the formation of procoagulant platelets without affecting amyloid fibril formation. Notably, when we used BAPTA to chelate calcium ions and T101 to inhibit intracellular Factor XIIIA in platelets, both treatments significantly suppressed the formation of amyloid fibrils and markedly reduced the generation of procoagulant platelets. Conclusions: Our study concludes that Aβ 1-42 has a stronger platelet-activating effect than Aβ 1-40 and promotes procoagulant platelet generation through amyloid fibril formation. Inhibiting calcium ions and platelet FXIII-A activity can reduce Aβ 1-42 aggregation and procoagulant platelet production. These findings could provide new therapeutic insights for Alzheimer’s disease.