Ahmed Touqeer, Zahid Saadia, Mahboob Aamra, Farhat Syeda Mehpara
Neurobiology Laboratory, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology P.O. Box: 44000, Sector H-12, Islamabad. Pakistan.
Curr Neuropharmacol. 2017;15(4):480-494. doi: 10.2174/1570159X14666160325121145.
Alzheimer's disease (AD) is the most common form of old age dementia. The formation of amyloid plaques (Aβ), neurofibrillary tangles and loss of basal forebrain cholinergic neurons are the hallmark events in the pathology of AD.
Cholinergic system is one of the most important neurotransmitter system involved in learning and memory which preferentially degenerates in the initial stages of AD. Activation of cholinergic receptors (muscarinic and nicotinic) activates multiple pathways which result in post translational modifications (PTMs) in multiple proteins which bring changes in nervous system. Cholinergic receptors-mediated PTMs "in-part" substantially affect the biosynthesis, proteolysis, degradation and expression of many proteins and in particular, amyloid precursor protein (APP). APP is subjected to several PTMs (proteolytic processing, glycosylation, sulfation, and phosphorylation) during its course of processing, resulting in Aβ deposition, leading to AD. Aβ also alters the PTMs of tau which is a microtubule associated protein. Therefore, post-translationally modified tau and Aβ collectively aggravate the neuronal loss that leads to cholinergic hypofunction.
Despite the accumulating evidences, the interaction between cholinergic neurotransmission and the physiological significance of PTM events remain speculative and still needs further exploration. This review focuses on the role of cholinergic system and discusses the significance of PTMs in pathological progression of AD and highlights some important future directions.
阿尔茨海默病（AD）是老年痴呆最常见的形式。淀粉样斑块（Aβ）的形成、神经原纤维缠结以及基底前脑胆碱能神经元的丧失是AD病理学中的标志性事件。
胆碱能系统是参与学习和记忆的最重要的神经递质系统之一，在AD的初始阶段优先退化。胆碱能受体（毒蕈碱型和烟碱型）的激活会激活多条途径，导致多种蛋白质发生翻译后修饰（PTM），从而引起神经系统的变化。胆碱能受体介导的PTM在很大程度上“部分地”影响许多蛋白质的生物合成、蛋白水解、降解和表达，特别是淀粉样前体蛋白（APP）。APP在加工过程中会经历几种PTM（蛋白水解加工、糖基化、硫酸化和磷酸化），导致Aβ沉积，进而引发AD。Aβ还会改变与微管相关的蛋白tau的PTM。因此，翻译后修饰的tau和Aβ共同加剧了导致胆碱能功能减退的神经元丧失。
尽管有越来越多的证据，但胆碱能神经传递与PTM事件的生理意义之间的相互作用仍具有推测性，仍需进一步探索。本综述重点关注胆碱能系统的作用，并讨论PTM在AD病理进展中的意义，同时强调一些重要的未来研究方向。
