Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
J Neurochem. 2011 Mar;116(5):742-6. doi: 10.1111/j.1471-4159.2010.07032.x. Epub 2011 Jan 12.
The early stages of Alzheimer's disease are characterized by cholinergic deficits and the preservation of cholinergic function through the use of acetylcholinesterase inhibitors is the basis for current treatments of the disease. Understanding the causes for the loss of basal forebrain cholinergic neurons in neurodegeneration is therefore a key to developing new therapeutics. In this study, we review novel aspects of cholinesterase membrane localization in brain and propose mechanisms for its lipid domain targeting, secretion and protein-protein interactions. In erythrocytes, acetylcholinesterase (AChE) is localized to lipid rafts through a GPI anchor. However, the main splice form of AChE in brain lacks a transmembrane peptide anchor region and is bound to the 'proline-rich membrane anchor', PRiMA, in lipid rafts. Furthermore, AChE is secreted ('shed') from membranes and this shedding is stimulated by cholinergic agonists. Immunocytochemical studies on rat brain have shown that membrane-associated PRiMA immunofluorescence is located selectively at cholinergic neurons of the basal forebrain and striatum. A strong association of AChE with the membrane via PRiMA seems therefore to be a specific requirement of forebrain cholinergic neurons. α7 nicotinic acetylcholine receptors are also associated with lipid rafts where they undergo rapid internalisation on stimulation. We are currently probing the mechanism(s) of AChE shedding, and whether this process and its apparent association with α7 nicotinic acetylcholine receptors and metabolism of the Alzheimer's amyloid precursor protein is determined by its association with lipid raft domains either in normal or pathological situations.
阿尔茨海默病的早期阶段以胆碱能缺陷为特征，通过使用乙酰胆碱酯酶抑制剂来维持胆碱能功能是目前治疗这种疾病的基础。因此，了解基底前脑胆碱能神经元在神经退行性变中丧失的原因是开发新疗法的关键。在这项研究中，我们回顾了脑内胆碱酯酶膜定位的新方面，并提出了其脂质域靶向、分泌和蛋白质-蛋白质相互作用的机制。在红细胞中，乙酰胆碱酯酶（AChE）通过糖基磷脂酰肌醇（GPI）锚定定位于脂筏。然而，脑中 AChE 的主要剪接形式缺乏跨膜肽锚区，与“富含脯氨酸的膜锚”（PRiMA）结合在脂筏中。此外，AChE 从膜上分泌（“脱落”），这种脱落受胆碱能激动剂的刺激。对大鼠脑的免疫细胞化学研究表明，膜相关的 PRiMA 免疫荧光选择性地位于基底前脑和纹状体的胆碱能神经元上。因此，AChE 通过 PRiMA 与膜的紧密结合似乎是前脑胆碱能神经元的一个特殊要求。α7 烟碱型乙酰胆碱受体也与脂筏相关，在受到刺激时，它们会迅速内化。我们目前正在探索 AChE 脱落的机制，以及这个过程及其与α7 烟碱型乙酰胆碱受体和阿尔茨海默病淀粉样前体蛋白代谢的明显关联是否取决于其与正常或病理情况下的脂筏域的关联。
