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Products of the Alzheimer's disease amyloid precursor protein generated by,ß-secretase are present in human platelets, and secreted upon degranulation

Roberto Cappai, PhD

Genevieve Evin, PhD

Jane E. Tanner, BSc

Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

Carol W. Gray, PhD

SmithKline Beecham Pharmaceuticals, Harlow, Essex, England

Konrad Beyreuther, PhD

Center for Molecular Biology, The University of Heidelberg, Germany

Colin L. Masters, MD

Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

Proteolytic processing of Alzheimer's disease amyloid precursor protein (APP) by /3-secretase generates the Nterminus ofA/3 (which deposits in the brain) and releases a secreted ectodomain of APP (sAPP/3). We identified in human platelets a band at 125 kDa corresponding to APP ectodomain ending with C-terminal methionine residue (APP⁶⁷¹) as characterized by an antibody specificfor the C-terminal methionine residue of sAPP/3. The same antibody also detected bands at -105 and U125 kDa in human brain homogenates. Platelet sAPP/3 is an isoform containing the Kunitzprotease inhibitor domain (sAPP/3-KPI+) and is released into the medium when platelets are induced to aggregate using agonists such as thrombin, collagen, phorbol 12-myristate 13-acetate, or calcium ionophore A2318 7. The release of sAPPB /from aggregatedplatelets is consistent with a role in regulation of the coagulation cascade and/or in platelet aggregation. These data together with previous reports suggest that human platelets contain the a-, /3-and y-secretase activities, and are a suitable system to study APP processing and Ap production, a pathway which is considered to be a prime targetfor therapeutic intervention in AD.

American Journal of Alzheimer's Disease and Other Dementias®, Vol. 13, No. 5, 236-244 (1998)
DOI: 10.1177/153331759801300504


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