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  • Title: Amyloid beta peptide-activated signal pathways in human platelets.
    Author: Shen MY, Hsiao G, Fong TH, Chen HM, Chou DS, Lin CH, Sheu JR, Hsu CY.
    Journal: Eur J Pharmacol; 2008 Jul 07; 588(2-3):259-66. PubMed ID: 18511035.
    Abstract:
    Amyloid beta peptide (amyloid-beta), which accumulates in the cerebral microvessels in an age-dependent manner, plays a key role in the pathogenesis of cerebral amyloid angiopathy. Platelets are an important cellular element in vasculopathy of various causes. Amyloid-beta may activate or potentiate platelet aggregation. The present study explored the signaling events that underlie amyloid-beta activation of platelet aggregation. Platelet aggregometry, immunoblotting and assays to detect activated cellular events were applied to examine the signaling processes of amyloid-beta activation of platelets. Exogenous amyloid-beta (1-2 microM) potentiated platelet aggregation caused by collagen and other agonists. At higher concentrations (5-10 microM), amyloid-beta induced platelet aggregation which was accompanied by an increase in thromboxane A2 (TxA2) formation. These amyloid-beta actions on platelets were causally related to amyloid-beta activation of p38 mitogen-activated protein kinase (MAPK). Inhibitors of p38 MAPK and its upstream signaling pathways including proteinase-activated receptor 1 (PAR1), Ras, phosphoinositide 3-kinase (PI3-kinase), or Akt, but not extracellular signal-regulated kinase 2 (ERK2)/c-Jun N-terminal kinase 1 (JNK1), blocked amyloid-beta-induced platelet activation. These findings suggest that the p38 MAPK, but not ERK2 or JNK1 pathway, is specifically activated in amyloid-beta-induced platelet aggregation with the following signaling pathway: PAR1 --> Ras/Raf --> PI3-kinase --> Akt --> p38 MAPK --> cytosolic phospholipase A2 (cPLA2)--> TxA2. In conclusion, this study demonstrates amyloid-beta activation of a p38 MAPK signaling pathway in platelets leading to aggregation. Further studies are needed to define the specific role of amyloid-beta activation of platelets in the pathogenesis of vasculopathy including cerebral amyloid angiopathy.
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