Metabolism of Alzheimer beta-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cell-free system.

Various compounds that affect signal transduction regulate the relative utilization of alternative processing pathways for the beta-amyloid precursor protein (beta APP) in intact cells, increasing the production of nonamyloidogenic soluble beta APP (s beta APP) and decreasing that of amyloidogenic beta-amyloid peptide. In a recent study directed toward elucidating the mechanisms underlying phorbol ester-stimulated s beta APP secretion from cells, it was demonstrated that protein kinase C increases the formation from the trans-Golgi network (TGN) of beta APP-containing secretory vesicles. Here we present evidence that forskolin increases s beta APP production from intact PC12 cells, and protein kinase A stimulates formation from the TGN of beta APP-containing vesicles. Although protein kinase A and protein kinase C converge at the level of formation from the TGN of beta APP-containing vesicles, additional evidence indicates that the regulatory mechanisms involved are distinct. IMAGES:

影响信号转导的多种化合物可调控完整细胞中β淀粉样前体蛋白（beta-amyloid precursor protein, βAPP）的选择性加工通路相对使用效率，提升非淀粉样变性可溶性βAPP（soluble beta APP, sβAPP）的生成量，同时减少淀粉样变性β淀粉样肽的产生。此前一项旨在阐明佛波酯介导细胞分泌sβAPP机制的研究证实，蛋白激酶C（protein kinase C, PKC）可促进反式高尔基网络（trans-Golgi network, TGN）中含βAPP的分泌囊泡形成。本研究提供证据表明，毛喉素（forskolin）可提升完整PC12细胞中sβAPP的生成量，且蛋白激酶A（protein kinase A, PKA）可促进反式高尔基网络中含βAPP的分泌囊泡形成。尽管蛋白激酶A与蛋白激酶C在含βAPP分泌囊泡的反式高尔基网络形成环节存在调控交汇，但额外实验证据显示二者所涉及的调控机制并不相同。IMAGES: