Inhibition of platelet activation by the Alzheimer's disease amyloid precursor protein.
The amyloid precursor protein (APP) of Alzheimer's disease is abundantly expressed in the platelet alpha-granule where its role remains unclear. This study describes a novel function for APP in regulating human platelet activation. Preincubation of platelet-rich plasma with recombinant secreted APP (sAPP) isoforms dose-dependently inhibited platelet aggregation and secretion induced by ADP or adrenaline. Similarly, sAPP potently inhibited low-dose thrombin-induced activation in washed platelet suspensions, indicating that the activity does not require plasma cofactors. There were no functional differences between sAPP forms with or without the Kunitz protease inhibitor domain or derived from either alpha- or beta-secretase cleavage. In fact, the N-terminal cysteine-rich region of APP (residues 18-194) was as effective as the entire sAPP region in the inhibition of platelet activation. The inhibitory activity of sAPP correlated with a significant reduction in the agonist-induced production of the arachidonic acid (AA) metabolites thromboxane B2 and prostaglandin E2. However, sAPP did not affect AA-induced platelet aggregation or secretion, indicating the enzymatic conversion of AA was not inhibited. The addition of a threshold dose of AA reversed the sAPP-inhibition of agonist-induced platelet activation. This suggests that sAPP decreases the availability of free AA, although the mechanism is not yet known. These data provide evidence that the release of sAPP upon platelet degranulation may result in negative feedback regulation during platelet activation.
Henry
A
A
Department of Pathology, University of Melbourne and Mental Health Research Institute of Victoria, Parkville, Australia.
Li
Q X
QX
Galatis
D
D
Hesse
L
L
Multhaup
G
G
Beyreuther
K
K
Masters
C L
CL
Cappai
R
R
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000544:Alzheimer Disease / Q000097:blood*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D018929:Cell Culture Techniques; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000037:antagonists & inhibitors; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000096:biosynthesis
D016564:Amyloid beta-Protein Precursor; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D013917:Thrombin; D015232:Dinoprostone; D004837:Epinephrine