Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain.
Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain.
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发表时间：
2002
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通讯作者：
J. Huse;Kangning Liu;D. S. Pijak;Dan Carlin;V. Lee;R. Doms
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作者：
J. Huse;Kangning Liu;D. S. Pijak;Dan Carlin;V. Lee;R. Doms
在阿尔茨海默病的大脑中积累的β -淀粉样蛋白（β -）肽来源于β和γ分泌酶活性对淀粉样蛋白前体蛋白的蛋白水解加工。β -分泌酶β -位点淀粉样蛋白前体蛋白切割酶（BACE）通过在Asp(1) （β -位点）或Glu(11) （β '-位点）上的切割产生A β的N端，最终产生全长A β 1-40/42或截断的A β 11-40/42。这种可变切割位点特异性的功能意义以及全长与n端截断的A β的相对病理影响在很大程度上仍然未知。在我们对细胞培养中BACE反应性的分析中，我们发现蛋白酶对β -或β '-切割的偏好强烈依赖于细胞内定位。在内质网中，β位点蛋白水解占主导地位，而在反式高尔基网络中，β′-裂解更受青睐。此外，BACE不同的切割位点特异性并不仅仅是由于细胞器pH值或相关糖蛋白的低聚糖组成的差异。尸检脑标本的检查显示，在不溶性淀粉样蛋白池中存在显著水平的A β 11-40/42。综上所述，这些数据支持β′-裂解在脑淀粉样蛋白沉积过程中的重要作用，并将加工事件定位于反式高尔基网络。
The amyloid beta (A beta) peptide that accumulates in Alzheimer's disease brain is derived from the proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase activities. The beta-secretase enzyme beta-site amyloid precursor protein-cleaving enzyme (BACE) generates the N terminus of A beta by cleavage at either Asp(1) (beta-site) or Glu(11) (beta'-site), ultimately leading to the production of full-length A beta 1-40/42 or truncated A beta 11-40/42. The functional significance of this variable cleavage site specificity as well as the relative pathological impact of full-length versus N-terminally truncated A beta remains largely unknown. In our analysis of BACE reactivity in cell culture, we found that the preference of the protease for either beta- or beta'-cleavage was strongly dependent on intracellular localization. Within the endoplasmic reticulum, beta-site proteolysis predominated, whereas in the trans-Golgi network, beta'-cleavage was favored. Furthermore, the contrasting cleavage site specificities of BACE were not simply due to differences in organelle pH or the oligosaccharide composition of the glycoproteins involved. Examination of post-mortem brain specimens revealed significant levels of A beta 11-40/42 within insoluble amyloid pools. Taken together, these data support an important role for beta'-cleavage in the process of cerebral amyloid deposition and localize the processing event to the trans-Golgi network.