POLARIZED SECRETION OF BETA-AMYLOID PRECURSOR PROTEIN AND AMYLOID BETA-PEPTIDE IN MDCK CELLS
POLARIZED SECRETION OF BETA-AMYLOID PRECURSOR PROTEIN AND AMYLOID BETA-PEPTIDE IN MDCK CELLS
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DOI：
10.1073/pnas.91.4.1564
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发表时间：
1994-02-15
影响因子：
11.1
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
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作者：
HAASS, C;KOO, EH;SELKOE, DJ
β-淀粉样前体蛋白(β-APP)是一种广泛表达的完整膜蛋白，经蛋白水解物处理后可产生多种分泌性衍生物，包括可溶性APP(S)、4-kDa淀粉样β蛋白(A-β)及其相关的3-kDa多肽(P3)。为了了解βAPP的运输和处理，我们分析了βAPP在Madin-Darby犬肾(MDCK)细胞中的分类，MDCK是一种已知具有生理上不同的顶端和基底外侧质膜的上皮细胞。βAPP的处理导致APP的高度极化分泌(S)。ABP 90%以上见于基底外侧室，不到10%见于根尖室。这与测试版APP在基侧卖出表面上的优先本地化有关。激活已知的促进APP(S)分泌的蛋白激酶C，并没有改变APP(S)的释放极性，但显著增加了分泌量。Aβ和p3多肽也主要在基底侧分泌。此外，MDCK细胞从Arg-5开始分泌截短形式的Aβ。这些数据表明，β-APP的蛋白分解加工产物经历了极化分泌。此外，结果表明，淀粉样变性Aβ多肽是在βAPP极化分选后产生的。在阿尔茨海默病期间，这些上皮细胞中Aβ的极化基底侧分泌为Aβ在脑微血管基底膜中的积聚提供了潜在的机制。
The beta-amyloid precursor protein (beta APP) is a widely expressed integral membrane protein that is proteolytically processed to yield several secreted derivatives, including soluble APP (APP(s)), the 4-kDa amyloid beta-peptide (A beta), and a related 3-kDa peptide (p3). To understand beta APP trafficking and processing, we analyzed the sorting of beta APP in Madin-Darby canine kidney (MDCK) cells, an epithelial cell known to possess physiologically distinct apical and basolateral plasma membranes. Processing of beta APP resulted in highly polarized secretion of APP(s). More than 90% of ABP, was detected in the basolateral compartment, and less than 10% was found in the apical compartment. This was associated with a preferential localization of beta APP on the basolateral sell surface. Activation of protein kinase C, which is known to enhance the secretion of APP(s), did not change the polarity of APP(s) release but significantly increased the amount secreted. A beta and p3 peptides were also secreted predominantly basolaterally. In addition, MDCK cells secreted a truncated form of A beta beginning at Arg-5. These data show that the proteolytic processing products of beta APP undergo polarized secretion. Moreover, the results suggest that the amyloidogenic A beta peptide is generated following the polarized sorting of beta APP. The polarized basolateral secretion of A beta in these epithelial cells provides a potential mechanism for the accumulation of A beta in the abluminal basement membrane of brain microvessels during Alzheimer disease.