A detergent-insoluble membrane compartment contains A beta in vivo.
A detergent-insoluble membrane compartment contains A beta in vivo.
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发表时间：
1998
期刊：
影响因子：
82.9
通讯作者：
S. J. Lee;U. Liyanage;P. Bickel;W. Xia;P. Lansbury;K. Kosik
中科院分区：
文献类型：
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作者：
S. J. Lee;U. Liyanage;P. Bickel;W. Xia;P. Lansbury;K. Kosik
淀粉样蛋白 (Aβ) 有序组装成淀粉样原纤维是阿尔茨海默病 (AD) 的关键步骤。为了从阿尔茨海默病淀粉样蛋白前体蛋白 (APP) 中释放淀粉样肽 Aβ，两种分泌酶依次起作用：首先，β 分泌酶在胞外域内靠近膜的位置进行切割，然后 γ 分泌酶在跨膜域内进行切割。 γ-分泌酶裂解位点位于 Aβ 的残基 40 或 42 之后。除了那些罕见的由突变引起的 AD 病例外，分泌的 Aβ 水平不会升高；因此，分泌途径可能不受影响，并且除了Aβ细胞外浓度之外的因素可能有助于肽的聚集特性。 β也存在于细胞内区室中。两种 γ-分泌酶裂解产物 A beta42 和 A beta40 存在于不同的区室中：A beta42 在内质网 (ER)/中间区室中，A beta40 在反高尔基体网络 (TGN) 中。含有 Aβ 的细胞区室是治疗干预的靶位点。在这里，我们报告说，在大脑中，Aβ 所在的主要区室是去污剂不溶性的富含糖脂的膜结构域 (DIG)。 DIG 级分中还存在早老素-1 (PS1) 和 APP 的内切蛋白水解片段。这些蛋白质的存在都有助于 Aβ 的生成，表明 DIG 部分可能是 APP 发生膜内裂解的地方。
Ordered assembly of the amyloid-beta protein (A beta) into amyloid fibrils is a critical step in Alzheimer's disease (AD). To release the amyloidogenic peptide A beta from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, beta-secretase cleaves close to the membrane within the ectodomain and then gamma-secretase cuts within the transmembrane domain. The sites of gamma-secretase cleavage are after residues 40 or 42 of A beta. Except in those rare cases of AD caused by a mutation, levels of secreted A beta are not elevated; thus, the secretory pathway may be unaffected, and factors other than the extracellular concentration of A beta may contribute to the aggregation properties of the peptide. A beta is also present in intracellular compartments. The two gamma-secretase cleavage products, A beta42 and A beta40, were found in different compartments: A beta42 in the endoplasmic reticulum (ER)/intermediate compartment, and A beta40 in the trans-Golgi network (TGN). The cellular compartments that harbor A beta are target sites for therapeutic intervention. Here we report that in the brain, the principal compartment in which A beta resides is a detergent-insoluble glycolipid-enriched membrane domain (DIG). Also present in the DIG fractions are the endoproteolytic fragments of presenilin-1 (PS1) and APP. The presence of these proteins, which all contribute to the generation of A beta, indicates that the DIG fraction is probably where the intramembranous cleavage of APP occurs.