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 beta-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.


CONCLUSIONS
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.
Greenberg
David S
DS
Department of Biological Chemistry, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, Israel.
Toiber
Debra
D
Berson
Amit
A
Soreq
Hermona
H
D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric
D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D012333:RNA, Messenger; D000110:Acetylcholinesterase