Abstract
The choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) are fundamental to neurophysiological functions of the central cholinergic system. We confirmed and quantified the presence of extracellular ChAT protein in human plasma and also characterized ChAT and VAChT polymorphisms, protein and activity levels in plasma of Alzheimer's disease patients (AD; N = 112) and in cognitively healthy controls (EC; N = 118). We found no significant differences in plasma levels of ChAT activity and protein between AD and EC groups. Although no differences were observed in plasma ChAT activity and protein concentration among ChEI-treated and untreated AD patients, ChAT activity and protein levels variance in plasma were higher among the rivastigmine-treated group (ChAT protein: p = 0.005; ChAT activity: p = 0.0002). Moreover, AD patients homozygous for SNP rs1880676 A allele exhibited higher levels of ChAT activity. Considering this is the first study to report the influence of genetic variability of CHAT locus over ChAT activity in AD patients plasma, it opens a new set of important questions on peripheral cholinergic signaling in AD.
Highlights
The central cholinergic system plays a fundamental role in memory and learning mechanisms, and cholinergic deficit in Alzheimer’s disease (AD) generates cognitive impairment (Bartus et al, 1982)
We found no significant differences in plasma levels of choline acetyltransferase (ChAT) activity and protein between Alzheimer’s disease patients (AD) and EC groups
No differences were observed in plasma ChAT activity and protein concentration among cholinesterase inhibitors (ChEIs)-treated and untreated AD patients, ChAT activity and protein levels variance in plasma were higher among the rivastigminetreated group (ChAT protein: p = 0.005; ChAT activity: p = 0.0002)
Summary
0.46 0.11 the action of IChEs, since the enzyme is modulated by the bioavailable Ach concentration. The plasma ChAT levels between the AD patients who were on ChEIs therapy, compared to those who were not, partially supported the above notion, since the variance of ChAT was different in those taking rivastigmine, which indicates a bidirectional influence of this drug on ChAT protein expression in the plasma This is interesting since BChE activity dominates in plasma, and rivastigmine is the only ChEI as AD therapeutic that inhibits both AChE and BChE with equal efficacy (Darreh-Shori et al, 2002). In addition the efficacy of inhibition by rivastigmine can greatly vary in different patients depending on variables such as tolerated dose and body weight, which in turn result in a large variation in the inhibition levels of these two enzymes This could express itself in a wide variation in the plasma ChAT expression as was seen among the rivastigmine-treated patients. More studies are required to confirm and expand the current findings
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