Cholinergic System and Post-translational Modifications: An Insight on the Role in Alzheimer's Disease

Abstract

Background: 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.

Literature review: 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.

Conclusion: 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.

Keywords: Acetylcholine; Alzheimer's disease; muscarinic receptors; nicotinic receptors; post translational modifications.

Fig. (1)

Expression of Muscarinic and Nicotinic Receptors in Brain. Abbreviations: bas: Nucleus basalis, Hippo: hippocampus, LC: locus coeruleus, PFC: Prefrontal cortex, SN: substantia nigra, VTA: ventral tegmental area [39, 40, 44, 51, 52, 76].

Fig. (2)

Cholinergic Synapse and PTMs of APP and Tau. Abbreviations: ChaT: Choline acetylTransferase, PtdCho: Phosphotidylcholine, SV: Synaptic vesicles, AChE: Acetylcholine esterase, ACh: acetylcholine, mAChR: muscarinic ACh receptor, nAChR: nicotinic ACh receptor, 1) PtdCho provides the choline precursor and acetyl moiety from acetyl CoA, 2) in the presence of ChaT 3) the ACh is synthesized, 4) Storage of ACh in synaptic vesicles, 5) Release of ACh in the synaptic cleft, 6) Action of ACh on postsynaptic cholinergic receptor, 7) Degradation of ACh via AChE into choline and acetate ion, 8) Reuptake of choline into the presynaptic nerve terminal by choline transporter.