Research and practice in thrombosis and haemostasis · 2023
Human platelets release amyloid peptides β1-40 and β1-42 in response to haemostatic, immune, and hypoxic stimuli.
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Wolska Nina, Celikag Meral, Failla Antonio Virgilio, Tarafdar Anuradha, Renné Thomas, Torti Mauro, Canobbio Ilaria, Pula Giordano
Аннотация
BACKGROUND: Platelets contain high levels of amyloid β (Aβ) peptides and have been suggested to participate in the deposition of amyloid plaques in Alzheimer's Disease (AD).
OBJECTIVES: This study aimed to determine whether human platelets release pathogenic Aβ peptides Aβ1-42 and Aβ1-40 and to characterise the mechanisms regulating this phenomenon.
METHODS AND RESULTS: Enzyme-linked immunosorbent assays (ELISAs) revealed that the haemostatic stimulus thrombin and the pro-inflammatory molecule lipopolysaccharide (LPS) induce platelet release of both Aβ1-42 and Aβ1-40. Notably, LPS preferentially induced the release of Aβ1-42, which was potentiated by the reduction of oxygen from atmospheric levels to physiological hypoxia. The selective β secretase (BACE) inhibitor LY2886721 showed no effect on the release of either Aβ1-40 or Aβ1-42 in our ELISA experiments. This suggested a store-and-release mechanism that was confirmed in immunostaining experiments showing co-localisation of cleaved Aβ peptides with platelet alpha granules.
CONCLUSIONS: Taken together, our data suggest that human platelets release pathogenic Aβ peptides as a result of a store-and-release mechanism rather than a de novo proteolytic event. Although further studies are required to fully characterise this phenomenon, we suggest the possibility of a role for platelets in the deposition of Aβ peptides and the formation of amyloid plaques. Interestingly, the combination of hypoxia and inflammation that we simulated in vitro with reduced oxygen tension and LPS may increase the release of fibrillogenic Aβ1-42 and, consequently, exacerbate amyloid plaque deposition in the brain of AD patients.
OBJECTIVES: This study aimed to determine whether human platelets release pathogenic Aβ peptides Aβ1-42 and Aβ1-40 and to characterise the mechanisms regulating this phenomenon.
METHODS AND RESULTS: Enzyme-linked immunosorbent assays (ELISAs) revealed that the haemostatic stimulus thrombin and the pro-inflammatory molecule lipopolysaccharide (LPS) induce platelet release of both Aβ1-42 and Aβ1-40. Notably, LPS preferentially induced the release of Aβ1-42, which was potentiated by the reduction of oxygen from atmospheric levels to physiological hypoxia. The selective β secretase (BACE) inhibitor LY2886721 showed no effect on the release of either Aβ1-40 or Aβ1-42 in our ELISA experiments. This suggested a store-and-release mechanism that was confirmed in immunostaining experiments showing co-localisation of cleaved Aβ peptides with platelet alpha granules.
CONCLUSIONS: Taken together, our data suggest that human platelets release pathogenic Aβ peptides as a result of a store-and-release mechanism rather than a de novo proteolytic event. Although further studies are required to fully characterise this phenomenon, we suggest the possibility of a role for platelets in the deposition of Aβ peptides and the formation of amyloid plaques. Interestingly, the combination of hypoxia and inflammation that we simulated in vitro with reduced oxygen tension and LPS may increase the release of fibrillogenic Aβ1-42 and, consequently, exacerbate amyloid plaque deposition in the brain of AD patients.