Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor.
Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor.
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发表时间：
1994-09
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通讯作者：
J. Davis-Salinas;S. Saporito-irwin;F. M. Donovan;Dennis Cunningham;W. E. Nostrand
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作者：
J. Davis-Salinas;S. Saporito-irwin;F. M. Donovan;Dennis Cunningham;W. E. Nostrand
淀粉样β蛋白（A β）和蛋白酶连接蛋白-2/淀粉样β蛋白前体（PN-2/A β PP）是阿尔茨海默病及相关疾病患者老年斑和脑血管沉积物的主要成分。有人认为凝血蛋白酶凝血酶可能以一种导致A β形成的方式加工A β PP。在这里，我们研究了凝血酶对细胞系统中PN-2/A β - PP的分泌和加工以及A - β的产生的影响。用凝血酶（1-5 nM）孵育胶质母细胞瘤细胞，可在培养基中积累异常加工的羧基末端截断形式的分泌PN-2/A β PP（约85 kDa）。在培养的未转染的胶质母细胞瘤细胞和稳定转染的胶质母细胞瘤细胞中，较高浓度的凝血酶（bbb10 nM）也增加了分泌PN-2/A β PP的水平，以过量产生A β PP的695异构体。将未转染和转染的胶质母细胞瘤细胞与凝血酶孵育导致培养液中可溶性A β水平降低，这与先前提出的PN-2/A β PP分泌机制一致。它对分泌的PN-2/A β PP的蛋白水解可能破坏分泌蛋白的羧基端附近的区域，这些区域解释了它们的神经保护和细胞粘附特性。
The amyloid beta-protein (A beta) and protease nexin-2/amyloid beta-protein precursor (PN-2/A beta PP) are major constituents of senile plaques and cerebrovascular deposits in individuals with Alzheimer's disease and related disorders. It has been suggested that the coagulation protease thrombin may process A beta PP in a manner leading to the formation of A beta. Here we investigated the effects of thrombin on the secretion and processing of PN-2/A beta PP and the production of A beta in a cellular system. Incubation of glioblastoma cells with thrombin (1-5 nM) resulted in the accumulation of abnormally processed, carboxyl-terminal-truncated forms of secreted PN-2/A beta PP (approximately 85 kDa) in the culture medium. Higher concentrations of thrombin (> 10 nM) also increased the levels of secreted PN-2/A beta PP in cultured untransfected glioblastoma cells and glioblastoma cells that were stably transfected to overproduce the 695 isoform of A beta PP. Increased secretion of PN-2/A beta PP 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 A beta in the culture medium consistent with previously suggested mechanisms regarding the secretion of PN-2/A beta PP. Although the present studies suggest that thrombin does not directly contribute to A beta formation, its proteolysis of secreted PN-2/A beta PP may disrupt regions near the carboxyl terminus of the secreted proteins that account for their neuroprotective and cell adhesive properties.