Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative.
Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative.
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DOI：
10.1016/s0021-9258(17)36875-8
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发表时间：
1994-05
期刊：
影响因子：
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通讯作者：
D. Gabuzda;J. Busciglio;Lanren Chen;P. Matsudaira;B. Yankner
中科院分区：
文献类型：
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作者：
D. Gabuzda;J. Busciglio;Lanren Chen;P. Matsudaira;B. Yankner
导致阿尔茨海默病中β淀粉样蛋白的产生和病理沉积的细胞机制尚不清楚。在这份报告中，我们描述了淀粉样前体蛋白（APP）的蛋白水解加工为11.5 kDa的COOH-末端衍生物，其中包含全长β淀粉样蛋白序列。该加工步骤通常以低水平与分泌途径中的APP成熟平行发生。抑制氧化能量代谢的叠氮化钠或线粒体解偶联剂羰基氰化物间氯苯腙增加了APP的蛋白水解的11.5 kDa的衍生物约80倍的积累，这种APP衍生物在高尔基复合体。在分泌途径中抑制蛋白质转运的试剂，包括莫能菌素和布雷菲德菌素A，也增加了11.5-kDa衍生物的产生。APP成熟的抑制表明，11.5-kDa的衍生物可以通过蛋白水解不成熟的APP。这些结果表明，APP加工到潜在的淀粉样蛋白生成COOH-末端衍生物发生在内质网或高尔基复合体，并可以调制的状态下的细胞能量代谢。最近在阿尔茨海默病患者的大脑皮层中发现了氧化能量代谢的缺陷。这些发现提高了能量相关代谢应激可能导致APP代谢改变并导致阿尔茨海默病淀粉样变性的可能性。
The cellular mechanisms which lead to the generation and pathological deposition of beta amyloid in Alzheimer's disease are unknown. In this report we describe the proteolytic processing of the amyloid precursor protein (APP) to an 11.5-kDa COOH-terminal derivative which contains the full-length beta amyloid sequence. This processing step normally occurs at low levels in parallel with APP maturation in the secretory pathway. Inhibition of oxidative energy metabolism by sodium azide or the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone increased the proteolysis of APP to the 11.5-kDa derivative by about 80-fold with accumulation of this APP derivative in the Golgi complex. Agents which inhibit protein transport in the secretory pathway, including monensin and brefeldin A, also increased the production of the 11.5-kDa derivative. Inhibition of APP maturation demonstrated that the 11.5-kDa derivative could be produced by proteolysis of immature APP. These results demonstrate that APP processing to potentially amyloidogenic COOH-terminal derivatives occurs in either the endoplasmic reticulum or Golgi complex and can be modulated by the state of cellular energy metabolism. Deficits in oxidative energy metabolism have recently been found in the cerebral cortex of patients with Alzheimer's disease. These findings raise the possibility that energy-related metabolic stress may lead to altered metabolism of APP and contribute to amyloidosis in Alzheimer's disease.