Carlson C D, Czilli D L, Gitter B D
Neuroscience Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianoapolis, IN USA.
Neurobiol Aging. 2000 Sep-Oct;21(5):747-56. doi: 10.1016/s0197-4580(00)00172-x.
Amyloid precursor protein (APP) is cleaved to neurotoxic/proinflammatory amyloid beta protein (Abeta) or to the neuroprotective secreted alpha-APPs. A balance in APP metabolism may influence the outcome between toxicity and protection to central nervous system (CNS) neurons in Alzheimer's disease. Treatment of U-373 MG astrocytoma cells with aggregated Abeta (1-40) decreases APP secretion into the medium to 10-30% of control values. This decreased secretion appears to be specific for APP since Abeta treatment causes an approximately 2-fold increase in interleukin-8 (IL-8) secretion. Abeta treatment also causes a 4- to 9-fold increase in total cell-associated APP. This increase is due to cellular retention of alpha secretase-cleaved APP and a 2-fold increase in mature full-length APP. These data suggest that deposition of aggregated Abeta may contribute to Alzheimer's-associated neurotoxicity by altering the metabolism of the APP protein. Abeta may exert harmful effects by decreasing the secretion of neuroprotective or neurotrophic APP and, in addition, by increasing intracellular full-length APP; thereby providing increased substrate for generation of amyloidogenic peptide within astrocytes.
淀粉样前体蛋白（APP）可被切割成具有神经毒性/促炎作用的β淀粉样蛋白（Aβ）或具有神经保护作用的分泌型α-APPs。APP代谢的平衡可能会影响阿尔茨海默病中枢神经系统（CNS）神经元毒性与保护作用之间的结果。用聚集的Aβ（1-40）处理U-373 MG星形细胞瘤细胞，可使培养基中APP的分泌减少至对照值的10%-30%。这种分泌减少似乎是APP特有的，因为Aβ处理会使白细胞介素-8（IL-8）的分泌增加约2倍。Aβ处理还会使细胞内总的APP增加4至9倍。这种增加是由于α分泌酶切割的APP在细胞内滞留以及成熟全长APP增加了2倍。这些数据表明，聚集的Aβ沉积可能通过改变APP蛋白的代谢而导致与阿尔茨海默病相关的神经毒性。Aβ可能通过减少神经保护或神经营养性APP的分泌以及增加细胞内全长APP来发挥有害作用，从而为星形胶质细胞内淀粉样生成肽的产生提供更多底物。
