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Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor.

1994; Elsevier BV; Volume: 269; Issue: 36 Linguagem: Inglês

10.1016/s0021-9258(17)31691-5

1083-351X

Judianne Davis-Salinas, Susan M. Saporito-Irwin, Frances Donovan, Dennis D. Cunningham, William E. Van Nostrand,

Enzyme Production and Characterization

From the ~~~~~e n t of M ~c r o b ~o ~o ~ and Mo~ecu~ar Genetics, College of ~e ~~i ~e , ~n ~u e r s ~t ~ of C ~l i f o r n ~~, Iruine, C a l i f o r n ~ 9 2 ~~7 -~~~~ The amyloid &protein (AP) and protease nexin-2l amyloid &protein precursor (PN-2/A#?PP) are m ~o r constituents of senile plaques and cerebrovascular deposits in individuals with Alzheimer's disease and related dis- orders.It has been suggested that the coagulation protease thrombin may process APPP in a manner leading to the formation of Ap.Here we investigated the effects of thrombin on the secretion and processing of PN-21 APPP and the production of A#? in a cellular system.Incubation of glioblastoma cells with thrombin ( 1 4 n ~) resulted in the accumulation of abnormally processed, carboxyl-terminal-truncated forms of secreted PN-21 A8PP ( 4 5 m a ) in the culture medium.Higher concentrations of thrombin (>IO m) also increased the levels of secreted PN-WAfiPP in cultured untransfected glioblastoma cells and glioblastoma cells that were stably transfected to overproduce the 695 isoform of APPP.Increased secretion of PN-21Af3PP required the proteolytic activity of thrombin, was induced by activation of the thrombin receptor by agonist peptides, and required activation of protein kinase C. Incubation of the untransfected and transfected glioblastoma cells with thrombin led to decreased levels of soluble AP in the culture medium consistent with previously suggested mechanisms regarding the secretion of PN-Z/A@PP.Although the present studies suggest that thrombin does not directly contribute to AB formation, its proteolysis of secreted PN-Z/A#?PP may disrupt regions near the carboxyl terminus of the secreted proteins that account for their neuroprotective and cell adhesive properties.Deposition of Apl in senile plaques within the neuropil and in the walls of cortical and leptomeningeal blood vessels is a hallmark of Alzheimer's disease (1-4).AP is p~oteolytic~ly derived Grants AGO0538 (to W. E. V. N.