Endoplasmic reticulum chaperones inhibit the production of amyloid-β peptides
Endoplasmic reticulum chaperones inhibit the production of amyloid-β peptides
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DOI：
10.1042/bj20061318
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发表时间：
2007-03-15
影响因子：
4.1
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Hoshino, Tatsuya;Nakaya, Tadashi;Mizushima, Tohru
β-淀粉样前体蛋白（APP）水解产生的β-淀粉样肽（amyloid-beta peptides）在阿尔茨海默病（Alzheimer's disease，AD）的发病机制中起重要作用。内质网（内质网）分子伴侣，如GRP 78（葡萄糖调节蛋白78），对内质网中的蛋白质质量控制做出了重大贡献。在本研究中，我们研究了各种ER分子伴侣过表达对培养细胞中A β产生的影响，该细胞产生突变型APP（APPsw）。过表达GRP 78或抑制其基础表达，分别降低和升高条件培养基中A β 40和A β 42的水平。GRP 78的共伴侣ERdj 3或ERdj 4的共表达刺激GRP 78的这种抑制作用。在其他ER分子伴侣的情况下，一些（150 kDa的氧调节蛋白和钙连接蛋白）而不是其他（GRP 94和钙网蛋白）的过表达抑制了A的产生。这些结果表明，某些ER分子伴侣是A β产生的有效抑制剂，并且ER分子伴侣的无毒诱导剂可能对AD治疗有益。GRP 78与APP免疫共沉淀，过表达GRP 78可抑制APP的成熟，提示GRP 78可直接与APP结合，抑制APP的成熟，从而抑制APP的蛋白水解。此外，在表达APPsw的转基因小鼠的皮质和海马中，与野生型小鼠相比，一些ER伴侣蛋白的mRNA上调。我们认为这种上调是针对A β的细胞保护性反应。
A beta (amyloid-beta peptides) generated by proteolysis of APP (beta-amyloid precursor protein), play an important role in the pathogenesis of AD (Alzheimer's disease). ER (endoplasmic reticulum) chaperones, such as GRP78 (glucose-regulated protein 78), make a major contribution to protein quality control in the ER. In the present study, we examined the effect of overexpression of various ER chaperones on the production of A beta in cultured cells, which produce a mutant type of APP (APPsw). Overexpression of GRP78 or inhibition of its basal expression, decreased and increased respectively the level of A beta 40 and A beta 42 in conditioned medium. Co-expression of GRP78's co-chaperones ERdj3 or ERdj4 stimulated this inhibitory effect of GRP78. In the case of the other ER chaperones, overexpression of some (150 kDa oxygen-regulated protein and calnexin) but not others (GRP94 and calreticulin) suppressed the production of A. These results indicate that certain ER chaperones are effective suppressors of A beta production and that non-toxic inducers of ER chaperones may be therapeutically beneficial for AD treatment. GRP78 was co-immunoprecipitated with APP and overexpression of GRP78 inhibited the maturation of APP, suggesting that GRP78 binds directly to APP and inhibits its maturation, resulting in suppression of the proteolysis of APP. On the other hand, overproduction of APPsw or addition of synthetic A beta 42 caused up-regulation of the mRNA of various ER chaperones in cells. Furthermore, in the cortex and hippocampus of transgenic mice expressing APPsw, the mRNA of some ER chaperones was up-regulated in comparison with wild-type mice. We consider that this upregulation is a cellular protective response against A beta.