Cook D G, Forman M S, Sung J C, Leight S, Kolson D L, Iwatsubo T, Lee V M, Doms R W
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Abramson Research Center, Philadelphia 19104, USA.
Nat Med. 1997 Sep;3(9):1021-3. doi: 10.1038/nm0997-1021.
Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid beta-peptide (A beta) derived from cleavage of the amyloid precursor protein (APP). Varying in length from 39 to 43 amino acids, A beta, particularly the longer A beta(42), is thought to play a significant role in AD pathogenesis. To better understand AD it is important to identify the subcellular organelles generating A beta. Studies using agents that disrupt endosomal/lysosomal function suggest that A beta is generated late in the secretory and endocytic pathways. However, much of what is known about A beta biosynthesis has been inferred by monitoring extracellular A beta levels since intracellular A beta is undetectable in most cell types. Consequently, the precise site or sites that generate A beta, or whether A beta(1-40) and A beta(1-42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular A beta(1-40), but did not alter intracellular A beta(1-42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of A beta.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是出现大量主要由淀粉样前体蛋白（APP）裂解产生的淀粉样β肽（Aβ）构成的血管和脑内斑块。Aβ长度在39至43个氨基酸之间变化，特别是较长的Aβ（42），被认为在AD发病机制中起重要作用。为了更好地理解AD，识别产生Aβ的亚细胞细胞器很重要。使用破坏内体/溶酶体功能的试剂进行的研究表明，Aβ在分泌和内吞途径的后期产生。然而，由于在大多数细胞类型中无法检测到细胞内Aβ，关于Aβ生物合成的许多知识都是通过监测细胞外Aβ水平推断出来的。因此，产生Aβ的确切位点，或者Aβ（1-40）和Aβ（1-42）是否在生物合成途径的同一点产生，尚不清楚。利用人NT2N神经元，我们发现通过三种独立方法将APP保留在内质网/中间区室（ER/IC）中可消除细胞内Aβ（1-40）的产生，但不会改变细胞内Aβ（1-42）的合成。这些发现表明，ER/IC可能是产生这种高度淀粉样变性的Aβ物种的重要位点。
