Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease.
One of the main hallmarks of Alzheimer's disease (AD) is the brain deposition of senile plaques made up of toxic amyloid beta-peptide (Abeta), which is derived from a larger protein called the beta-amyloid precursor protein (APP). Both APP processing and cholinesterase activity are affected in the AD brain, but, yet, cholinesterase inhibitors (ChEI) remain the primary Food and Drug Administration approved drugs for AD within the United States. Herein, we evaluated the effects of two clinically relevant drugs on the APP pathway, which is presumably involved in AD pathogenesis. Specifically, we compared the actions of the classical ChEI physostigmine (PHY) and its analog phenserine (PHE) on neuronal cell viability, on IC50 and on levels of different amyloid proteins. Interestingly, these drugs share the same chemical backbone, inhibit acetylcholinesterase with similar potency, but differentially affect APP processing. PHE treatment decreased levels of APP in the human neuroblastoma cells (p=0.009) whereas PHY showed a similar but less-pronounced trend, which did not attain statistical significance. PHE treatment significantly decreased levels of Abeta in human neuroblastoma cells (p=0.02) whereas PHY showed no significant change under the same conditions. The divergent actions of these two structurally related drugs on the amyloid pathway indicate that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other.
Lahiri
Debomoy K
DK
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dlahiri@iupui.edu
Alley
George M
GM
Tweedie
David
D
Chen
Demao
D
Greig
Nigel H
NH
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007211:Indoles; D011758:Pyrroles; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C092280:phenserine