Abstract Body: 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.