Department of Biological Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, Israel.
Neurodegener Dis. 2010;7(1-3):60-3. doi: 10.1159/000285507. Epub 2010 Feb 18.
In Alzheimer's disease (AD), cholinergic neurons are particularly vulnerable for as yet unclear reasons. Here, we report that modified composition, localization and properties of alternative splice variants encoding the acetylcholine-hydrolyzing enzyme acetylcholinesterase (AChE) may be variably involved in disease progression or in systemic efforts to attenuate its progression.
The purpose of this study was to explore the implications for AD of the cellular and biochemical properties of the various AChE proteins, differing in their N and C termini.
We have used cell transfection with genetically engineered vectors as well as microinjection to overexpress specific AChE variants and explore the consequences to cellular well-being and survival. Additionally, we employed highly purified recombinant AChE-R and AChE-S to explore putative interactions with the AD beta-amyloid peptide.
Our findings demonstrate distinct, and in certain cases inverse cell fate outcome under enforced expression of the human N- and C-terminally modified AChE variants, all of which have similar enzymatic activities.
The N-terminal extension in conjunction with the primary helical C-terminal peptide of 'tailed' AChE-S facilitates, whereas the shorter, naturally unfolded C-terminus of the stress-induced AChE-R variant attenuates Alzheimer's pathology.
在阿尔茨海默病（AD）中，胆碱能神经元特别容易受到影响，但其原因尚不清楚。在这里，我们报告说，乙酰胆碱水解酶乙酰胆碱酯酶（AChE）的编码基因的剪接变体的组成、定位和特性的改变可能与疾病的进展或系统地减轻其进展有关。
本研究的目的是探讨不同 N 和 C 末端的各种 AChE 蛋白的细胞和生化特性对 AD 的影响。
我们使用基因工程载体的细胞转染以及微注射来过表达特定的 AChE 变体，并探讨对细胞健康和存活的影响。此外，我们还使用高度纯化的重组 AChE-R 和 AChE-S 来探索与 AD β-淀粉样肽的潜在相互作用。
我们的研究结果表明，在强制表达人 N 和 C 末端修饰的 AChE 变体时，会出现明显的、在某些情况下相反的细胞命运结果，所有这些变体都具有相似的酶活性。
“长尾”AChE-S 的 N 端延伸与主要螺旋 C 端肽结合，促进了阿尔茨海默病病理学的发生，而应激诱导的 AChE-R 变体的较短、天然无规则的 C 端则减弱了阿尔茨海默病病理学的发生。
