Cellular mechanisms of β-amyloid production and secretion
Cellular mechanisms of β-amyloid production and secretion
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DOI：
10.1073/pnas.96.20.11049
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发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Lieberburg, I
中科院分区：
文献类型：
--
作者：
Sinha, S;Lieberburg, I
阿尔茨海默病老年斑的主要成分是一种42-AA多肽，称为β-淀粉样蛋白(Aβ)，Aβ是由一系列差异剪接的、含有1型跨膜结构域(TM)的蛋白质(APP)通过内蛋白降解过程产生的。在细胞培养中，APP代谢的主要、相对普遍的途径包括α-分泌酶的裂解，它在Aβ序列中裂解，从而阻止Aβ的形成和沉积。另一条分泌途径，富含在神经元和大脑中，导致APP被β-分泌酶切割在Aβ肽的N端，从而产生细胞相关的β-C末端片段(β-CTF)。APP(APP“瑞典”)密码子670/671处的致病突变导致β-分泌酶剪切键的切割增强，Aβ的形成增加。空泡ATPase的抑制剂巴非霉素选择性地抑制细胞培养中的β-分泌酶的作用，这表明需要一个酸性的细胞内隔室才能有效地裂解APP。β-CTF在TM区域被伽玛分泌酶(S)切割，同时产生Aβ1-40(90%)和AP 1-42(10%)，APP密码子717(APP伦敦)的致病突变导致产生和分泌Aβ1-42的比例增加。位于14号染色体上的PS-1错义突变在大多数家族性阿尔茨海默病家系中是致病的，这些突变还导致Aβ1-42的产生比Aβ1-40的产生增加，在转基因动物中PS-1的敲除导致原代培养的Aβ1-40和Aβ1-42的产生显著抑制，表明PS-1的表达对伽玛分泌酶裂解是重要的，已发现的多肽醛抑制剂通过抑制β-CTF的g-分泌酶裂解来阻断Aβ的产生。
The major constituent of senile plaques in Alzheimer's disease is a 42-aa peptide, referred to as beta-amyloid (A beta), A beta is generated from a family of differentially spliced, type-1 transmembrane domain (TM)-containing proteins, called APP, by endoproteolytic processing. The major, relatively ubiquitous pathway of APP metabolism in cell culture involves cleavage by alpha-secretase, which cleaves within the A beta sequence, thus precluding A beta formation and deposition, An alternate secretory pathway, enriched in neurons and brain, leads to cleavage of APP at the N terminus of the A beta peptide by beta-secretase, thus generating a cell-associated beta-C-terminal fragment (beta-CTF). A pathogenic mutation at codons 670/671 in APP (APP "Swedish") leads to enhanced cleavage at the beta-secretase scissile bond and increased A beta formation. An inhibitor of vacuolar ATPases, bafilomycin, selectively inhibits the action of beta-secretase in cell culture, suggesting a requirement for an acidic intracellular compartment for effective beta-secretase cleavage of APP, beta-CTF is cleaved in the TM domain by gamma-secretase(s), generating both A beta 1-40 (90%) and AP 1-42 (10%), Pathogenic mutations in APP at codon 717 (APP "London") lead to an increased proportion of A beta 1-42 being produced and secreted. Missense mutations in PS-1, localized to chromosome 14, are pathogenic in the majority of familial Alzheimer's pedigrees, These mutations also lead to increased production of A beta 1-42 over A beta 1-40, Knockout of PS-1 in transgenic animals leads to significant inhibition of production of both A beta 1-40 and A beta 1-42 in primary cultures, indicating that PS-1 expression is important for gamma-secretase cleavages, Peptide aldehyde inhibitors that block A beta production by inhibiting g-secretase cleavage of beta-CTF have been discovered.