The brain-derived neurotrophic factor prompts platelet aggregation and secretion
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Blood advances
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American Society of Hematology
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Organisme subventionnaire
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Brain-derived neurotrophic factor (BDNF) has both autocrine and paracrine roles in
neurons, and its release and signaling mechanisms have been extensively studied in the
central nervous system. Large quantities of BDNF have been reported in circulation,
essentially stored in platelets with concentrations reaching 100- to 1000-fold those of neurons. Despite this abundance, the function of BDNF in platelet biology has not been
explored. At low concentrations, BDNF primed platelets, acting synergistically with classical agonists. At high concentrations, BDNF induced complete biphasic platelet aggregation
that in part relied on amplification from secondary mediators. Neurotrophin-4, but not
nerve growth factor, and an activating antibody against the canonical BDNF receptor
tropomyosin-related kinase B (TrkB) induced similar platelet responses to BDNF, suggesting
TrkB could be the mediator. Platelets expressed, both at their surface and in their intracellular compartment, a truncated form of TrkB lacking its tyrosine kinase domain. BDNFinduced platelet aggregation was prevented by inhibitors of Ras-related C3 botulinum toxin
substrate 1 (Rac1), protein kinase C, and phosphoinositide 3-kinase. BDNF-stimulated platelets secreted a panel of angiogenic and inflammatory cytokines, which may play a role in
maintaining vascular homeostasis. Two families with autism spectrum disorder were
found to carry rare missense variants in the BDNF gene. Platelet studies revealed defects in
platelet aggregation to low concentrations of collagen, as well as reduced adenosine triphosphate secretion in response to adenosine diphosphate. In summary, circulating BDNF
levels appear to regulate platelet activation, aggregation, and secretion through activation
of a truncated TrkB receptor and downstream kinase-dependent signaling.
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