GENERATION OF BETA-AMYLOID IN THE SECRETORY PATHWAY IN NEURONAL AND NONNEURONAL CELLS
GENERATION OF BETA-AMYLOID IN THE SECRETORY PATHWAY IN NEURONAL AND NONNEURONAL CELLS
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DOI：
10.1073/pnas.90.5.2092
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发表时间：
1993-03-01
影响因子：
11.1
通讯作者：
YANKNER, BA
中科院分区：
文献类型：
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作者：
BUSCIGLIO, J;GABUZDA, DH;YANKNER, BA
阿尔茨海默病中β-淀粉样蛋白生成的细胞机制及其与淀粉样蛋白前体蛋白正常代谢的关系尚不清楚。在本报告中，我们表明源自淀粉样前体蛋白的 3-和 4-kDa 肽是正常分泌的。表位作图和放射性标记序列分析表明，4-kDa 肽与全长 β-淀粉样蛋白密切相关，而 3-kDa 种类是一组在 β-淀粉样蛋白 N 末端截短的异质肽。 β-淀粉样肽与淀粉样前体蛋白同时分泌。高尔基体加工抑制剂抑制β-淀粉样肽的分泌，而溶酶体抑制剂则没有作用。 β-淀粉样蛋白相关肽的分泌发生在多种细胞类型中，但产生哪些肽及其绝对水平取决于细胞类型。人类星形胶质细胞产生的β-淀粉样蛋白水平高于所检测的任何其他细胞类型。这些结果表明β-淀粉样蛋白是在分泌途径中产生的，并提供证据表明神经胶质细胞是大脑中β-淀粉样蛋白产生的主要来源。
The cellular mechanism underlying the generation of beta-amyloid in Alzheimer disease and its relationship to the normal metabolism of the amyloid precursor protein are unknown. In this report, we show that 3- and 4-kDa peptides derived from amyloid precursor protein are normally secreted. Epitope mapping and radiolabel sequence analysis suggest that the 4-kDa peptide is closely related to full-length beta-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the beta-amyloid N terminus. The beta-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of beta-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of beta-amyloid-related peptides occurs in a wide variety of cell types, but which peptides are produced and their absolute levels are dependent on cell type. Human astrocytes generated higher levels of beta-amyloid than any other cell type examined. These results suggest that beta-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of beta-amyloid production in the brain.