Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer's amyloid peptide, A beta 1-42, in differentiated PC12 cells
Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer's amyloid peptide, A beta 1-42, in differentiated PC12 cells
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DOI：
10.1016/s0006-8993(96)01262-0
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发表时间：
1997-01-23
期刊：
影响因子：
2.9
通讯作者：
Glabe, CG
中科院分区：
文献类型：
--
作者：
Burdick, D;Kosmoski, J;Glabe, CG
阿尔茨海默病(AD)的一个中心问题是淀粉样蛋白在发病机制中的作用。最近的发现表明，较长的Aβ1-42形式的淀粉样蛋白在发病机制中的作用导致我们描述了Aβ与细胞的相互作用，以阐明可能解释这些观察到的差异的原因。我们表征了放射性标记的Aβ在NGF分化的PC12细胞中的吸附、内化和降解，条件是没有急性毒性。所有被研究的Aβ多肽都吸附在PC12细胞表面并被内化，但Aβ1-42的吸附和内化明显大于Aβ1-40和Aβ1-28。神经氨酸酶处理的细胞对Aβ1-42的吸附减少，但肝素酶处理细胞不减少。内化的Aβ1-42与较短的Aβ1-42的命运也有很大的不同：内化的Aβ1-42的一部分在细胞内积累，至少可耐降解3天，而Aβ1-40及更短的多肽被消除，半衰期约为1小时。Aβ1-42似乎不抑制溶酶体水解酶，因为在存在或不存在Aβ1-42的情况下，Aβ1-28的降解速度相同。细胞内的Aβ1-42位于一个密集的细胞器内，与溶酶体标记荧光黄和辣根过氧化物酶共存。这些数据表明，与Aβ1-40和Aβ1-28相比，Aβ1-42在细胞表面的吸附、内化和分解代谢有显著差异。这些差异可能是优先积累较长的Aβ1-42亚型及其与AD发病相关的重要因素。
A central question in Alzheimer's disease (AD) is the role of amyloid in pathogenesis. Recent discoveries implicating the longer A beta 1-42 form of amyloid in pathogenesis led us to characterize the interaction of A beta with cells to elucidate differences that might account for these observations. We characterized the adsorption, internalization and degradation of radiolabeled A beta in NGF-differentiated PC12 cells under conditions that are not acutely toxic. All A beta peptides examined adsorb to the surface of PC12 cells and are internalized; however the adsorption and internalization of A beta 1-42 is significantly greater than that of A beta 1-40 and A beta 1-28. The adsorption of A beta 1-42 is decreased by treatment of the cells with neuraminidase, but not heparitinase. The fate of the internalized A beta 1-42 is also very different than shorter A beta peptides: a fraction of the internalized A beta 1-42 accumulates intracellularly and is resistant to degradation for at least 3 days while A beta 1-40 and shorter peptides are eliminated with a half life of about 1 h. A beta 1-42 does not appear to inhibit lysosomal hydrolases, since A beta 1-28 is degraded at the same rate in the presence or absence of A beta 1-42. The intracellular A beta 1-42 is located in a dense organellar compartment and colocalizes with the lysosomal markers Lucifer Yellow and horseradish peroxidase. These data indicate that there are significant differences in the cell surface adsorption, internalization and catabolism of A beta 1-42 compared to A beta 1-40 and A beta 1-28. These differences may be important for the preferential accumulation of the longer A beta 1-42 isoform and its association with AD pathogenesis.