Hartmann T, Bieger S C, Brühl B, Tienari P J, Ida N, Allsop D, Roberts G W, Masters C L, Dotti C G, Unsicker K, Beyreuther K
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Germany.
Nat Med. 1997 Sep;3(9):1016-20. doi: 10.1038/nm0997-1016.
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 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.
阿尔茨海默病淀粉样前体蛋白（APP）可被多种蛋白酶切割，其中研究最多但仍未明确的是那些参与释放APP片段（即淀粉样β蛋白Aβ）的蛋白酶。γ-分泌酶介导的蛋白水解是产生Aβ的最后一步加工过程。切割发生在Aβ的第40位残基之后[Aβ(1-40)]，偶尔也会在第42位残基之后[Aβ(1-42)]。即使这种Aβ(1-42)的量稍有增加，可能就足以引发阿尔茨海默病（AD）（参考文献1、2中有综述）。因此，人们普遍认为抑制这种酶可能有助于预防AD。出乎意料的是，我们在神经元中发现内质网（ER）是产生Aβ(1-42)的场所，而反式高尔基体网络（TGN）是产生Aβ(1-40)的场所。有趣的是，Aβ的细胞内产生似乎是神经元所特有的，因为我们发现非神经元细胞仅在细胞表面产生大量的Aβ(1-40)和Aβ(1-42)。神经元内质网中关键的Aβ异构体的特异性产生将这个区室与Aβ的产生联系起来，并解释了为什么主要定位于内质网的（突变）蛋白（如早老素）会诱发AD。我们认为AD中最早发生的事件可能是内质网中Aβ(1-42)的产生。
