Non-cholinergic, trophic action of recombinant acetylcholinesterase on mid-brain dopaminergic neurons

Abstract

Acetylcholinesterase (AChE) is secreted from various brain regions such as the substantia nigra, where levels of this molecule are disproportionately higher than those of choline acetyltransferase. It is thus possible that AChE may have alternative, non-cholinergic functions, one of which could be in development. Indeed, several recent studies have already demonstrated a neurotrophic action of AChE independent of hydrolysis of acetylcholine. In the developing nervous system the dominant forms of AChE differ from the tetramers (G4) that prevail in maturity, in that they are lower molecular weight monomers (G1) and dimers (G2). Therefore, the aims of this study were to explore the neurotrophic role of AChE by comparing the effects of mouse recombinant G1 and G4 AChE on the survival and development of mid-brain tyrosine hydroxylase immunoreactive neurons. Butyrylcholinesterase (BuChE), which also hydrolyses acetylcholine, and basic fibroblast growth factor (bFGF), an established trophic factor for midbrain neurons, were also tested. bFGF had no significant stimulatory effect: moreover, BuChE was also inefficacious, suggesting that the action of AChE was independent of its catalytic site. In contrast, mouse recombinant G1 and G4 AChE both increased the survival as well as the outgrowth of the cultured neurons. However, G1 AChE was more potent than G4 AChE suggesting that developmental forms of AChE exist. The implications of this finding for physiological and pathological functioning of the nervous system are discussed.

Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission

“…AChE application to the medium induces the extension of neuronal processes, synapse formation, and AMPA receptor surface expression in hippocampal cell cultures (Olivera et al 2003). Some reports claim a more potent role for the embryonic AChE-S monomers than for the adult tetramers (Holmes et al 1997;Day and Greenfield 2002); however, others contest these observations (De Jaco et al 2002a,b). Importantly, Xenopus tadpoles overexpressing human AChE-R do not show more extensive neurite outgrowth than control tadpoles, suggesting that AChE membrane attachment is essential to influence such processes.…”

Regulation of the rat oligodendroglia cell line OLN‐93 by antisense transfection of butyrylcholinesterase

“…There is ample evidence that both types of cholinesterases have nonenzymatic side functions. For AChE, a cell adhesive function independent of its enzymatic activity has been firmly established (Layer et al, 1993;Willbold and Layer, 1994;Jones et al, 1995;Small et al, 1995;Holmes et al, 1997;Koenigsberger et al, 1997;Sharma and Bigbee, 1998;Sternfeld et al, 1998).…”

Functional redundancy of acetylcholinesterase and neuroligin in mammalian neuritogenesis

“…1). An evolutionarily conserved capacity of AChE to promote process extension was observed in avian, amphibian, and mammalian primary neurons (2)(3)(4) and in rat glioma cells (5). In neuroblastoma cells, modulated expression of AChE revealed a direct correlation between AChE levels and neurite outgrowth (6).…”

“…However, the molecular and cellular mechanism(s) by which AChE exerts its neuritogenic activities remain to be elucidated. Repeated observations that process-promoting activities of AChE are insensitive to certain active site inhibitors (2,3) and to genetically engineered inactivation of its hydrolytic activity (4) demonstrated their noncatalytic nature. Together with the sequence homologies observed for AChE and several known cell-adhesion proteins, these findings hinted at a role for AChE in cell adhesionrelated processes.…”