Distinct sites of intracellular production for Alzheimer's disease A beta 40/42 amyloid peptides
Distinct sites of intracellular production for Alzheimer's disease A beta 40/42 amyloid peptides
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DOI：
10.1038/nm0997-1016
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发表时间：
1997-09-01
期刊：
影响因子：
82.9
通讯作者：
Beyreuther, K
中科院分区：
文献类型：
--
作者：
Hartmann, T;Bieger, SC;Beyreuther, K
阿尔茨海默氏症淀粉样前体蛋白（APP）被几种蛋白酶切割，研究最多但仍未确定的是那些参与APP片段（淀粉样β蛋白A β）释放的蛋白酶。γ-分泌酶的蛋白水解是导致A β释放的最后一个加工步骤。切割发生在A β [A β（1-40）]的残基40之后，偶尔发生在残基42 [A β（1-42）]之后。这种A β（1-42）的量即使稍微增加，也可能足以引起阿尔茨海默病（AD）（参考文献1，2）。因此，一般认为，抑制这种酶可以帮助预防AD。出乎意料的是，我们已经在神经元中鉴定出内质网（ER）作为A β（1-42）产生的位点，并且反式高尔基体网络（TGN）作为A β（1-40）产生的位点。有趣的是，A β的细胞内生成似乎是神经元所独有的，因为我们发现非神经元细胞仅在细胞表面产生大量的A β（1-40）和A β（1-42）。神经元ER中关键A β同种型的特异性产生将该区室与A β的产生联系起来，并解释了为什么主要ER定位（突变）蛋白如早老素（3）可以诱导AD。我们认为AD最早发生的事件可能是ER中A β（1-42）的产生。
The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic beta-protein A beta. Proteolysis by gamma-secretase is the last processing step resulting in release of A beta. Cleavage occurs after residue 40 of A beta [A beta(1-40)], occasionally after residue 42 [A beta(1-42)]. Even slightly increased amounts of this A beta(1-42) might be sufficient to cause Alzheimer's disease (AD) (reviewed in ref. 1, 2). It is thus generally believed that inhibition of this enzyme could aid in prevention of AD. Unexpectedly we have identified in neurons the endoplasmic reticulum (ER) as the site for generation of A beta(1-42) and the trans-Golgi network (TGN) as the site for A beta(1-40) generation. It is interesting that intracellular generation of A beta seemed to be unique to neurons, because we found that nonneuronal cells produced significant amounts of A beta(1-40) and A beta(1-42) only at the cell surface. The specific production of the critical A beta isoform in the ER of neurons links this compartment with the generation of A beta and explains why primarily ER localized (mutant) proteins such as the presenilins(3) could induce AD. We suggest that the earliest event taking place in AD might be the generation of A beta(1-42) in the ER.