Acetylcholinesterase variants in Alzheimer's disease: From neuroprotection to programmed cell death

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.