We analyzed whether donepezil differently influences acetylcholinesterase (AChE) variants from cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) after long-term treatment. Overall CSF-AChE activity in AD patients before treatment was not different from controls, but the ratio between the major tetrameric form, G4, and the smaller G1 and G 2 species was significantly lower. AChE levels at study outset were found to correlate positively with β-amyloid 1-42 (Aβ42). When patients were re-examined after 12 months treatment with donepezil, there was a remarkable increase in both the G4 and the lighter species of CSF AChE. As compared with placebo, donepezil caused decreases in the percentage of AChE that failed to bind to the lectin concanavalin A and the antibody AE1. These non-binding species comprised primarily a small subset of G1 and G2 forms. In treated patients, these light variants were the only subset of CSF AChE that correlated with CSF-Aβ42 levels. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that a 77-kDa band, attributed in part to inactive AChE, was lower in AD patients than in controls. Unlike enzyme activity, the intensity of this band did not increase after donepezil treatment. The varying responses of different AChE species to ChE-I treatment suggest different modes of regulation, which may have therapeutic implications.
- Acetylcholinesterase variants
- Alzheimer's disease
- Cerebrospinal fluid
- Cholinesterase inhibitor
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience