Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.
Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.
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DOI：
10.1073/pnas.90.20.9513
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发表时间：
1993-10
影响因子：
11.1
通讯作者：
A. Wertkin;R. S. TURNERt;Samuel J. Pleasure;Todd E. GOLDEt;Steven G. Younkint;J. Trojanowski;Virginia M.-Y. Lee
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文献类型：
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作者：
A. Wertkin;R. S. TURNERt;Samuel J. Pleasure;Todd E. GOLDEt;Steven G. Younkint;J. Trojanowski;Virginia M.-Y. Lee
在阿尔茨海默病(AD)大脑细胞外间隙中以丝状聚集体形式聚集的β-淀粉样蛋白或β/A4肽来自一个或多个选择性剪接的淀粉样前体蛋白(APP)。中枢神经系统中含量更丰富的APP是695-(APP695)、751-(APP751)和770-(APP770)氨基酸亚型，每一种APP都可能是积累在AD大脑中的β/A4肽的来源。中枢神经系统神经元对这些APP代谢的改变可能会导致β/A4肽在脑实质中的释放和沉积。因此，我们研究了维甲酸处理后来自畸胎癌细胞系(NTera2/c1.d1或NT2细胞)的几乎纯人类神经元(NT2N细胞)中三种主要脑APP的表达和处理。NT2N神经元几乎只表达APP695，而NT2细胞主要表达APP751/770。此外，在NT2N细胞中APP的处理不同于NT2细胞和非神经细胞。最重要的是，NT2N神经元而不是NT2细胞构成地产生细胞内的β/A4肽并将其释放到培养基中。这项工作证实了细胞内β/A4肽的产生，并提示培养的NT2N细胞可能为理解神经元和APP695在AD脑中淀粉样蛋白形成中的作用提供了一个独特的模型系统。
The beta-amyloid or beta/A4 peptides that accumulate as filamentous aggregates in the extracellular space of Alzheimer disease (AD) brains are derived from one or more alternatively spliced amyloid precursor proteins (APPs). The more abundant APPs in the central nervous system are the 695-(APP695), 751- (APP751), and 770- (APP770) amino acid isoforms, and each could be the source of beta/A4 peptide that accumulates in the AD brain. It is plausible that altered metabolism of these APPs by central nervous system neurons could lead to the release and deposition of beta/A4 peptide in brain parenchyma. Thus, we examined the expression and processing of the three major brain APPs in nearly pure human neurons (NT2N cells) derived from a teratocarcinoma cell line (NTera2/c1.D1 or NT2 cells) after retinoic acid treatment. NT2N neurons expressed almost exclusively APP695, whereas NT2 cells expressed predominantly APP751/770. Furthermore, the processing of the APPs in NT2N cells was distinct from NT2 and nonneuronal cells. Most significantly, the NT2N neurons but not the NT2 cells constitutively generated intracellular beta/A4 peptide and released it into the culture medium. This work demonstrates the intracellular production of beta/A4 peptide and suggests that cultured NT2N cells may provide a unique model system for understanding the contribution of neurons and APP695 to amyloidogenesis in the AD brain.