Differential processing and secretion of Aβ peptides and sAPPα in human platelets is regulated by thrombin and prostaglandine 2

Abstract 

Metabolic and functional studies of the amyloid precursor protein (APP) in platelets have advanced our understanding of Alzheimer's disease (AD). Here we report that human platelets contain Aβ peptides, process and secrete them constitutively. Platelets generate formerly unkown Aβ-species by differential processing of APP. Release of Aβ peptides were also increased by platelet activation with thrombin, indicating the existence of a regulated exocytotic pathway. We showed that Aβ-levels, Aβ-processing patterns and Aβ-release kinetics were regulated by thrombin. In controls, release of Aβ peptide species (Aβ 1-40/42 and 1-37/38/39/) continued for more than 4h, while thrombin activated cells ceased secretion after 1h at large. Treatment of platelets with prostaglandine 2 slowed this process down. Intracellular Aβ peptide concentrations decreased steadily until no peptides could be detected after 20h (control) or after 4h (thrombin) in cultured platelets.

Abbreviations: EGTA, ethylene-diamin-tetra-acidic acid, Aβ, beta-amyloid peptide, APP, amyloid precursor protein, sAPPα, secreted APP after α-secretase cutting, sAPPα-like, secreted APPα-like protein family, PGE₂, prostaglandin 2, CSF, cerebrospinal fluid, Aβ-SDS-PAGE/immunoblot, polyacrylamide gel electrophoresis with sodium dodecyl sulfate and with urea, with following immunoblot of amyloidal peptide, SDS, sodium dodecyl sulfate, PAGE, polyacrylamide-gel-electrophoresis, %T, %C, where %T: the total acrylamid monomer concentration (w/v), %C: amount of N,N′-methylenbisacrylamide per total amount of acrylamide monomer (w/v)

Keywords: β-Amyloid peptides, Human platelets, sAPPα, Exocytosis