Long-lasting acetylcholinesterase splice variations in anticholinesterase-treated Alzheimer's disease patients.
Protein levels of different acetylcholinesterase (AChE) splice variants were explored by a combination of immunoblot techniques, using two different antibodies, directed against the C-terminus of the AChE-R splice variant or the core domain common to all variants. Both AChE-R and AChE-S splice variants as well as several heavier AChE complexes were detected in brain homogenates from the parietal cortex of patients with or without Alzheimer's disease (AD) as well as the cerebrospinal fluid (CSF) of AD patients, compatible with the assumption that CSF AChEs might originate from CNS neurons. Long-term changes in the composition of CSF AChE variants were further pursued in AD patients treated with rivastigmine (n = 11) or tacrine (n = 17) in comparison to untreated AD patients (n = 5). In untreated patients, AChE-R was markedly reduced as compared with the baseline level (37%), whereas the medium size AChE-S complex was increased by 32%. Intriguingly, tacrine produced a general and profound up-regulation of all detected AChE variants (up to 117%), whereas rivastigmine treatment caused a mild and selective up-regulation of AChE-R ( approximately 10%, p < 0.05). Moreover, the change in the ratio of AChE-R to AChE-S (R/S-ratio) strongly and positively correlated with sustained cognition at 12 months (p < 0.0001). Thus, evaluation of changes in the composition of CSF AChE variants may yield important information referring to the therapeutic efficacy and/or development of drug tolerance in AD patients treated with anti-cholinesterases.
Karolinska Institute, Neurotec Department, Stockholm, Sweden.
T
T
Darreh-Shori
E
E
Hellström-Lindahl
C
C
Flores-Flores
Z Z
ZZ
Guan
H
H
Soreq
A
A
Nordberg
D000110:Acetylcholinesterase / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D000368:Aged; D017398:Alternative Splicing / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015153:Blotting, Western; D002219:Carbamates / Q000627:therapeutic use; D002499:Centrifugation, Density Gradient; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000201:enzymology; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000175:diagnosis; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D010296:Parietal Lobe / Q000737:chemistry / Q000201:enzymology; D048448:Phenylcarbamates; D000068836:Rivastigmine; D013619:Tacrine / Q000627:therapeutic use; D013995:Time
D002219:Carbamates; D002556:Cerebrospinal Fluid Proteins; D002800:Cholinesterase Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D013619:Tacrine; D000110:Acetylcholinesterase; D000068836:Rivastigmine