Acetylcholinesterase Variants in Alzheimer’s Disease: From Neuroprotection to Programmed Cell Death

Abstract

Background: 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. Objective: 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. Methods: 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 β-amyloid peptide. Results: 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. Conclusion: 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.

Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

“…AChE expression was suppressed by the same si-RNA treatments. Although the down--regulation of AChE could represent a compensatory neuroprotective response (Noh, Koh et al 2009) to decreased ChAT, instead it could represent a damaging effect leading to increased apoptosis (Greenberg, Toiber et al 2010). Transfection of CNS neurons with si-InR or si-IGF-2R inhibited Tau gene expression, while siInR increased pTau immunoreactivity.…”

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.…”

“…Synaptic AChE-S (also called AChE-T with "T" indicating tailed) is the main transcript expressed in the nervous system (Evron et al 2007). AChE-S overexpression is linked to the intensification of the neurodeterioration (Birikh et al 2003) and programmed cell death (Greenberg et al 2010;Toiber et al 2009). On the other hand, a neuroprotective role has been ascribed to AChE-R in aging-dependent neuronal decline as well as neuropathologies, such as Aβ-induced AD .…”

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

“…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.…”

“…A neuro-protective role has been ascribed to AChE-R in age-dependent neuronal decline as well as in neuro-pathologies, such as AD (Berson et al, 2008). AChE-S overexpression has been also linked to intensification of neuro-deterioration (Birikh et al, 2003), programmed cell death (Greenberg et al, 2010;Toiber et al, 2009) and cell death of basal forebrain cholinergic neurons (Del Pino et al, 2014. Moreover, a selective loss of the tetrameric AChE form as observed after CPF exposure (Lopez-Granero et al, 2013b) has been related with neurodegenerative disorders, such as AD (Saez-Valero et al, 1999).…”