Alcadein Cleavages by Amyloid β-Precursor Protein (APP) α- and γ-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzheimer Disease-related γ-Secretase Dysfunction
Alcadein Cleavages by Amyloid β-Precursor Protein (APP) α- and γ-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzheimer Disease-related γ-Secretase Dysfunction
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DOI：
10.1074/jbc.m109.057497
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Suzuki, Toshiharu
中科院分区：
文献类型：
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作者：
Hata, Saori;Fujishige, Sayaka;Suzuki, Toshiharu
Alcadeins（Alcs）构成神经元I型膜蛋白家族，命名为Alc（alpha）、Alc（beta）和Alc（gamma）。Alcs主要表达于神经元中，并与脑中的阿尔茨海默淀粉样前体蛋白（APP）共定位。Alc和APP显示出与驱动蛋白-1的货物受体相同的功能。此外，Alc蛋白的蛋白水解加工似乎与APP的高度相似。我们发现APP α-分泌酶ADAM 10和ADAM 17主要切割Alc蛋白，并通过早老素依赖性γ-分泌酶复合物触发Alc C-末端片段的后续二次膜内切割，从而产生“APP p3样”和非聚集性Alc肽（p3-Alcs）。我们测定了人脑脊液中p3-Alc（alpha）、p3-Alc（beta）和p3-Alc（gamma）的完整氨基酸序列，其主要种类分别包含35、37和31个氨基酸。我们在这里证明，变体p3-Alc C末端受FAD相关的早老素1突变的调节，增加了次要β-淀粉样蛋白A β 42，这些突变改变了次要p3-Alc物质的水平。然而，p3-Alc（α）、p3-Alc（β）和p3-Alc（γ）的C-末端改变的幅度并不相等，这表明一种类型的γ-分泌酶功能障碍在I型膜蛋白的裂解中并不等同地出现在表型中。因为这些C-末端改变在人脑脊液中是可检测的，所以使用包括Alcs和APP的底物组可能有效地检测阿尔茨海默病受试者的发病前状态中的γ-分泌酶功能障碍。
Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). Wedetermined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species A beta 42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.