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J. Biol. Chem., Vol. 276, Issue 20, 17036-17043, May 18, 2001
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From The Center for Experimental Therapeutics and The Center for
Neurodegenerative Disease Research, University of Pennsylvania School
of Medicine, Philadelphia, Pennsylvania 19104
The main component of Alzheimer's disease (AD)
senile plaques is amyloid-
Amyloid Precursor Protein and Amyloid
Peptide in Human
Platelets
ROLE OF CYCLOOXYGENASE AND PROTEIN KINASE C*
,
peptide (A), a proteolytic fragment of
the amyloid precursor protein (APP). Platelets contain both APP and
A and may contribute to the perivascular amyloid deposition seen in AD. However, no data are available concerning the biochemical mechanism(s) involved in their formation and release by these cells. We
found that human platelets released APP and A following activation
with collagen or arachidonic acid. Inhibition of platelet cyclooxygenase (COX) reduced APP but not A release following those
stimuli. In contrast, activation of platelets by thrombin and calcium
ionophore caused release of both APP and A in a COX-independent fashion. Ex vivo studies showed that, despite suppression
of COX activity, administration of aspirin did not modify A or APP
levels in serum or plasma, suggesting that this enzyme plays only a
minor role in vivo. We examined the regulation of APP
cleavage and release from activated platelets and found that cleavage
requires protein kinase C (PKC) activity and is regulated by the
intracellular second messengers phosphatidylinositol 2-phosphate
and Ca2+. Our data provide the first evidence that in human
platelets COX is a minor component of APP secretion whereas PKC plays a major role in the secretory cleavage of APP. By contrast, A release may represent secretion of preformed peptide and is totally independent of both COX and PKC activity.
*
This work was supported in part by grants from NIA, National
Institutes of Health Grant AG11542 and the American Heart Association.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Medical Scientist Training Program Predoctoral
Fellowship from the National Institutes of Health.
§
To whom correspondence should be addressed: Center for Experimental
Therapeutics, 812 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-6446; Fax: 215-573-9004; E-mail:
domenico@spirit.gcrc.upenn.edu.
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