ABSTRACT
I. Introduction.......................................................................................................................... 203 II. Background.......................................................................................................................... 204
A. Butyrylcholinesterase Functions as a Natural Bioscavenger....................................... 204 B. Definition of Amyloid-b Peptides ............................................................................... 205 C. Toxic Ab Protofibrils Precede Plaque Formation ....................................................... 205
III. Methodology ........................................................................................................................ 206 A. Enzymes ....................................................................................................................... 206 B. Peptides ........................................................................................................................ 206 C. Kinetics of Ab Fibril Formation Monitored by Fluorescence Measurements ............ 206 D. Circular Dichroism Measurements .............................................................................. 206 E. Peptide Modeling......................................................................................................... 207
IV. Outcome and Discussion ..................................................................................................... 207 A. Circulation Butyrylcholinesterase Levels Increase with Age...................................... 207 B. Butyrylcholinesterase Attenuates Fibril Formation in a Dose Dependent Manner..... 208 C. Butyrylcholinesterase-Ab Interactions Affect Its Catalytic Properties....................... 209 D. Synaptic Acetylcholinesterase and Butyrylcholinesterase Have High Homology
but Distinct Peripheral Anionic Sites and C Termini.................................................. 210 E. Structural Modeling Implications ................................................................................ 211 F. Aromaticity Considerations ......................................................................................... 213 G. Inverse Roles for Butyrylcholinesterase and Synaptic Acetylcholinesterase
in Fibril Formation....................................................................................................... 213 H. Therapeutic Considerations.......................................................................................... 213
V. Summary and Conclusions .................................................................................................. 214 Acknowledgments......................................................................................................................... 214 References ..................................................................................................................................... 215
The reaction of alcohols and phosphoric acid yields organophosphate (OP) molecules that prevent the breakdown of the neurotransmitter acetylcholine (ACh) through inhibition of the hydrolytic activity of acetylcholinesterase (AChE). OPs were initially aimed to fight insects, but further
developments turned them into chemical weapons (Gallo and Lawryk, 1991; Chambers et al., 2001). Within the central nervous system and in the neuromuscular junctions, AChE is vital for the transmission of cholinergic impulses. A closely similar enzyme, butyrylcholinesterase (BChE) is also capable of hydrolyzing ACh. It has been suggested that human BChE from plasma participates in the endogenous scavenging of naturally occurring drugs (e.g., physostigmine, cocaine), manmade therapeutics (e.g., succinylcholine), as well as anticholinesterase-based pesticides and chemical warfare agents (Raveh et al., 1993, 1997; Jbilo et al., 1994; Schwarz et al., 1995; Sun et al., 2002; Giacobini, 2004), and as such serves as an inherent protector from the short-term damages caused by neurotoxic agents (Glick et al., 2003). Consequently, BChE administration was proposed as a putative prophylactic and therapeutic treatment of OP-poisoned subjects (Doctor and Saxena, 2005). Preclinical studies in various experimental animal models (rats, mice, and monkeys) supported the notion that this treatment may be palliatively successful (Ashani et al., 1991; Doctor and Saxena, 2005). However, the dangers of OP poisoning are not limited to the immediate effects, and it remained unclear whether BChE administration per se would not entail long-term damages. This question became particularly important in view of findings that synaptic acetylcholinesterase (AChE-S) exacerbates the formation of amyloid fibrils, the primary neuropathology characteristic of Alzheimer’s disease (AD) (Inestrosa et al., 1996a, 1996b, 2005; Rees et al., 2003, 2005).
