Neuronal AChE splice variants and their non‐hydrolytic functions: redefining a target of AChE inhibitors?

Abstract

AChE enzymatic inhibition is a core focus of pharmacological intervention in Alzheimer's disease (AD). Yet, AChE has also been ascribed non‐hydrolytic functions, which seem related to its appearance in various isoforms. Neuronal AChE presents as a tailed form (AChE‐T) predominantly found on the neuronal synapse, and a facultatively expressed readthough form (AChE‐R), which exerts short to medium‐term protective effects. Notably, this latter form is also found in the periphery. While these non‐hydrolytic functions of AChE are most controversially discussed, there is evidence for them being additional targets of AChE inhibitors. This review aims to provide clarification as to the role of these AChE splice variants and their interplay with other cholinergic parameters and their being targets of AChE inhibition: AChE‐R is particularly involved in the mediation of (anti‐)apoptotic events in cholinergic cells, involving adaptation of various cholinergic parameters and a time‐dependent link to the expression of neuroprotective factors. The AChE‐T C‐terminus is central to AChE activity regulation, while isolated AChE‐T C‐terminal fragments mediate toxic effects via the α7 nicotinic acetylcholine receptor. There is direct evidence for roles of AChE‐T and AChE‐R in neurodegeneration and neuroprotection, with these roles involving AChE as a key modulator of the cholinergic system: in vivo data further encourages the use of AChE inhibitors in the treatment of neurodegenerative conditions such as AD since effects on both enzymatic activity and the enzyme's non‐hydrolytic functions can be postulated. It also suggests that novel AChE inhibitors should enhance protective AChE‐R, while avoiding the concomitant up‐regulation of AChE‐T.

Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration

“…Caspase 3/7 activation was observed at the same range of concentrations which confirms cell viability results and suggests that apoptosis took place. These results are similar to previous works that show that CPF induced cell death through apoptosis (Caughlan et al, 2004;Ki et al, 2013;Saez-Valero et al, 1999), although necrosis could also contribute to the observed effect as was also previously reported (Zimmermann, 2013).…”

“…In this regard, under stress conditions, such as OPs exposure (Evron et al, 2007;Perrier et al, 2005), the transcription of the AChE-R has been reported to be increased (Adamec et al, 2008;Farchi et al, 2007). Some studies have associated this increase with a neuroprotective and repair role, whereas AChE-S overexpression, either by itself or when up-regulated in conjunction with AChE-R, is linked to programmed cell death (Greenberg et al, 2010;Zimmermann, 2013). Thus, the increase of AChE-S could be de cause of the apoptotic cell death observed and the increase of AChE-R be a neuroprotective mechanism against the harmful effects induced by AChE-S overexpression.…”

Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels

“…ACTB was used as an internal control. ***p < 0.001, significantly different from controls AChE-R decreased expression with an excess of the synaptic AChE-S has been associated with neurodeterioration and cell death (Birikh et al 2003;Greenberg et al 2010;Zimmermann 2013). Thus, this could explain the more pronounced cell death observed in our previous reported results mediated by AChE overexpression.…”

Intracellular distribution of 3,6-bis(3-alkylguanidino)acridines determines their cytotoxicity

“…AChE is responsible for the termination of cholinergic transmission (breakdown of acetylcholine) [42,43]. Two isoforms of AChE are synthesized in neuroblastoma cells, AChE-T (AChE-T, a tailed form of AChE) is linked to the cellular membrane and its soluble splice variant, AChE-R, is realeased into the cell media [44][45][46][47][48][49]. Thus acetylcholinesterase has been proposed as a potential target.…”