INHIBITION OF PLATELET ACTIVATION BY THE ALZHEIMERS-DISEASE AMYLOID PRECURSOR PROTEIN

The amyloid precursor protein (APP) of Alzheimer's disease is abundant ly expressed in the platelet alpha-granule where its role remains uncl ear. This study describes a novel function for APP in regulating human platelet activation. Preincubation of platelet-rich plasma with recom binant secreted APP (sAPP) isoforms dose-dependently inhibited platele t aggregation and secretion induced by ADP or adrenaline. Similarly, s APP potently inhibited low-dose thrombin-induced activation in washed platelet suspensions, indicating that the activity does not require pl asma cofactors. There were no functional differences between sAPP form s with or without the Kunitz protease inhibitor domain or derived from either alpha- or beta-secretase cleavage. In fact, the N-terminal cys teine-rich region of APP (residues 18-194) was as effective as the ent ire sAPP region in the inhibition of platelet activation. The inhibito ry activity of sAPP correlated with a significant reduction in the ago nist-induced production of the arachidonic acid (AA) metabolites throm boxane B-2 and prostaglandin E-2 However, sAPP did not affect Ail-indu ced platelet aggregation or secretion, indicating the enzymatic conver sion of AA was not inhibited. The addition of a threshold dose of AA r eversed the sAPP-inhibition of agonist-induced platelet activation. Th is suggests that sAPP decreases the availability of free AA, although the mechanism is not yet known. These data provide evidence that the r elease of sAPP upon platelet degranulation may result in negative feed back regulation during platelet activation.