App and alzheimer

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THE JOURNAL OF BIOLOCK!AL CHEMEXRY 0 1990 by The American Society for Biochemistry

and Molecular Biology, Inc.

Vol. 265, No. 26, Issue of September 15, pp. 15977-15963,199O Printed in U.S.A.

The Amyloid Precursor Human Platelets*

Protein of Alzheimer’s

Disease Is Released by
(Received for publication, March 22, 1990)

Ashley I. Bush$Oll, Ralph N. Martins& Baden MilwardS, JonCurrieB, David Amesn, Andreas Konrad Beyreuther 11,and Colin L. Masters$$**

Rumble$, Robert MoirS, Stephanie Fuller+, Elizabeth Weidemannll , Peter Fischer 11,Gerd Multhaup 11,
Research Institute, Royal Park Hospital, Royal Melbourne HospitaZ, Victoria 3050, Heidelberg, Federal Republic of Germany

From the $Department of Pathology, University of Melbourne, the §Mental Health Parkuille 3052,Austra&a, the llDepartment of Psychiatry, University of Melbourne, Australia, and the 11 Center for Molecular Biology, University of Heidelberg, D-6900

Western blots of normal human platelets, employing a monoclonal antibody raised against the full-length amyloid precursor protein of Alzheimer’s disease (APPssS), revealed major bands of 100-110 and 120130 kDa in both cytosolic, membrane, andreleased fractions. These species were similar in size to forms seen in brain preparations and in plasma. There was no difference in Western blots of platelet preparations from Alzheimer patients compared with controls. Purified platelet amyloid precursor proteins were sequenced and shown to be amino terminally homogeneous. Immunohistochemistry localized the antigen to the platelet and megakaryocyteand demonstrated weak immunostaining of some lymphocytes. Immunoprecipitation of material released from platelets demonstrated that sedimentable full-length APP with the carboxyl-terminal epitope, and soluble APP lacking the carboxyl-terminal epitope, may exist in the circulation. Western blots and carboxyl-terminal and amino-terminal APP radioimmunoassay of material released by platelets inresponse to stimulation revealed that platelets release APP during degranulation. The function of platelet APP is yet to be determined, but the present studies suggest a role in regulation of the coagulation cascade or in platelet aggregation.

in the transmembrane region and in part in the adjacent extracellular domain. The APP gene is located on chromosome 21, within or near the boundary of 21q21and 21q22.1 (Goldgaber et al., 1987; Kang et al., 1987; Robakis et al., 1987a, 1987b; Tanzi et al., 1987; Van Broekhoven et al., 1987; Zabel et al., 1987). At least five different mRNAs could be generated by alternate splicing, and some of these are expressed as a complex family of 92135-kDa membrane-bound and soluble glycoproteins. The prototype is APPeg5(Kang et al., 1987), and APPTG1 APPTTO andare isoforms achieved by the insertion of a serine protease inhibitory domain of the Kunitz type II family (Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et aZ., 1988). APPT14and APPTTO contain an OX-2-related domain (Kitaguchi et aZ., 1988; Golde et aZ.,1989). APPTslhas been shown to be identical with protease nexin-II which is secreted from human fibroblasts (Van Nostrand and Cunningham,1987) and forms inhibitory complexes with trypsin (Oltersdorf et al., 1989) and chymotrypsin (Van Nostrand et al, 1989). The postulated splice product APPsG3 homologous to APPTslbut is carboxyl is terminally truncated and therefore could yield a non-amyloidogenic secreted form (De Sauvage and Octave, 1989). APP is found in human brain and cerebrospinal fluid (Weidemann et al, 1989), rat brain (Card etal., 1988) and human kidney, spleen, heart, and adrenal tissues, but not in blood leukocytes or erythrocytes (Selkoe et al., 1988). Carboxylterminal immunoreactivity is found in human serum where there is an elevation in Down’s syndrome (Rumble et al., Alzheimer’s disease (AD)’ is an idiopathic progressive de- 1989). Northern blot analysis has detected mRNA in brain, mentia affecting a large...