Butyrylcholinesterase: An Important New Target in Alzheimer's Disease Therapy

Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options.

[1]  E. Giacobini,et al.  Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit , 2002, Journal of Neural Transmission.

[2]  K. Krishnan,et al.  Long-term effects of rivastigmine in moderately severe Alzheimer's disease Does early initiation of therapy offer sustained benefits? , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[3]  S. Potkin,et al.  Impact of Alzheimer's disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease , 2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[4]  M. Mesulam,et al.  Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine , 2002, Neuroscience.

[5]  Marsel Mesulam,et al.  Widely Spread Butyrylcholinesterase Can Hydrolyze Acetylcholine in the Normal and Alzheimer Brain , 2002, Neurobiology of Disease.

[6]  B. Vellas,et al.  Efficacy and Safety of Rivastigmine in Patients with Alzheimer's Disease who Failed to Benefit from Treatment with Donepezil , 2002, Current medical research and opinion.

[7]  A. Smith,et al.  Using meta-analysis to explain the diversity of results in genetic studies of late-onset Alzheimer’s disease and to identify high-risk subgroups , 2001, Neuroscience.

[8]  N. Greig,et al.  Methyl analogues of the experimental Alzheimer drug phenserine: synthesis and structure/activity relationships for acetyl- and butyrylcholinesterase inhibitory action. , 2001, Journal of medicinal chemistry.

[9]  N. Greig,et al.  Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Xiaoxiang Zhu,et al.  A New Therapeutic Target in Alzheimer's Disease Treatment: Attention to Butyrylcholinesterase , 2001, Current medical research and opinion.

[11]  O. Combarros,et al.  The butyrylcholinesterase K variant is a protective factor for sporadic Alzheimer's disease in women , 2000, Acta neurologica Scandinavica.

[12]  N. Greig,et al.  Cholinesterase inhibitors, β‐amyloid precursor protein and amyloid β‐peptides in Alzheimer's disease , 2000 .

[13]  N. Greig,et al.  The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics , 2000, Acta neurologica Scandinavica. Supplementum.

[14]  S. Brimijoin,et al.  Abundant Tissue Butyrylcholinesterase and Its Possible Function in the Acetylcholinesterase Knockout Mouse , 2000, Journal of neurochemistry.

[15]  P. Taylor,et al.  Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. , 2000, The Journal of pharmacology and experimental therapeutics.

[16]  R. Edwards,et al.  Donepezil Overdose: A Tenfold Dosing Error , 1999, The Annals of pharmacotherapy.

[17]  C. Jm,et al.  Symptomatic sinus bradycardia associated with donepezil , 1999 .

[18]  N. Greig,et al.  Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease. , 1999, Journal of medicinal chemistry.

[19]  H. Wiebusch,et al.  Further evidence for a synergistic association between APOEɛ4 and BCHE-K in confirmed Alzheimer’s disease , 1999, Human Genetics.

[20]  L. Schneider,et al.  Systematic review of the efficacy of rivastigmine for patients with Alzheimer's disease , 1998 .

[21]  Bruce A. Yankner,et al.  Aging renders the brain vulnerable to amyloid β-protein neurotoxicity , 1998, Nature Medicine.

[22]  B. Gulanski,et al.  Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease , 1998, Neurology.

[23]  D. Hopkins,et al.  Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation , 1998, The Journal of comparative neurology.

[24]  R. Polinsky,et al.  Dose‐dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease , 1998, Acta neurologica Scandinavica.

[25]  S. Gray,et al.  Donepezil Use in Alzheimer Disease , 1998, The Annals of pharmacotherapy.

[26]  A. Smith,et al.  Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. , 1997, Human molecular genetics.

[27]  P. Layer.  Non-classical actions of cholinesterases: Role in cellular differentiation, tumorigenesis and Alzheimer's disease , 1996, Neurochemistry International.

[28]  Claudia Linker,et al.  Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme , 1996, Neuron.

[29]  D. Ingram,et al.  Maze learning in aged rats is enhanced by phenserine, a novel anticholinesterase. , 1995, Neuroreport.

[30]  C. Geula,et al.  Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia , 1994, Annals of neurology.

[31]  B. L. Du,et al.  Human Cholinesterases and Anticholinesterases , 1994 .

[32]  C. Geula,et al.  Neuroglial cholinesterases in the normal brain and in Alzheimer's disease: Relationship to plaques, tangles, and patterns of selective vulnerability , 1993, Annals of neurology.

[33]  H. Soreq,et al.  Human Cholinesterases and Anticholinesterases , 1993 .

[34]  T. Arendt,et al.  Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development—A study of molecular forms , 1992, Neurochemistry International.

[35]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[36]  E. Stopa,et al.  Basic fibroblast growth factor in Alzheimer's disease. , 1990, Biochemical and biophysical research communications.

[37]  J. Marquis,et al.  Molecular forms of acetylcholinesterase in subcortical areas of normal and Alzheimer disease brain , 1990, Biological Psychiatry.

[38]  D. Nochlin,et al.  The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. , 1988, The American journal of pathology.

[39]  M. Mattson.  Neurotransmitters in the regulation of neuronal cytoarchitecture , 1988, Brain Research Reviews.

[40]  D. Quinn,et al.  Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states , 1987 .

[41]  E. Perry,et al.  Molecular Forms of Acetylcholinesterase and Butyrylcholinesterase in the Aged Human Central Nervous System , 1986, Journal of neurochemistry.

[42]  V. Bigl,et al.  DECREASED RATIO OF CSF ACETYLCHOLINESTERASE TO BUTYRYLCHOLINESTERASE ACTIVITY IN ALZHEIMER'S DISEASE , 1984, The Lancet.

[43]  R. Nicoll,et al.  Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells. , 1983, Science.

[44]  E. Perry,et al.  CHANGES IN BRAIN CHOLINESTERASES IN SENILE DEMENTIA OF ALZHEIMER TYPE , 1978, Neuropathology and applied neurobiology.

[45]  E. Mufson,et al.  Colocalization of cholinesterases with β amyloid protein in aged and Alzheimer's brains , 2004, Acta Neuropathologica.

[46]  Nigel H. Greig,et al.  Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease , 2002, NeuroMolecular Medicine.

[47]  E. Giacobini.  Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer's disease? , 2001, Drugs & aging.

[48]  Y. Agid,et al.  Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. , 1999, BMJ.

[49]  J. M. Calvo-Romero,et al.  [Symptomatic sinus bradycardia associated with donepezil]. , 1999, Revista de neurologia.

[50]  N. Greig,et al.  Induction, Secretion, and Pharmacological Regulation of β-App in Animal Model Systems , 1998 .

[51]  P Taylor,et al.  The cholinesterases: from genes to proteins. , 1994, Annual review of pharmacology and toxicology.

[52]  J. Massoulie,et al.  The molecular forms of cholinesterase and acetylcholinesterase in vertebrates. , 1982, Annual review of neuroscience.