Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development—A study of molecular forms

Arendt, Thomas; Brückner, Martina K.; Lange, Matthias; Bigl, Volker

doi:10.1016/0197-0186(92)90189-x

Cited by 297 publications

(223 citation statements)

References 91 publications

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“…31 In the AD brain, a selective reduction in the level of the G4 form occurs, whereas the level of the G1 form remains unchanged or increases. 29,32 This effect is most pronounced in the cortex and hippocampus, which are severely affected in AD. Therefore, a preferential affinity for G1 AChE, as seen with rivastigmine, may contribute to greater activity in the brain areas most affected in AD.…”

Section: Selectivity For Different Molecular Forms Of Cholinesterasementioning

confidence: 99%

“…28 The importance of BuChE in cholinergic neurotransmission is likely to increase in AD because as the disease progresses, AChE activity decreases by up to 45%, and BuChE activity increases by 40% to 90%. 27,29 Results with rivastigmine show that cognitive improvements (measured using the computerized neuropsychologic test battery) correlate independently with the inhibition of AChE and BuChE in the cerebrospinal fluid of AD patients, 30 suggesting that inhibition of both enzymes is a highly desirable feature of AD therapy.…”

Section: Key Pharmacologic Characteristics Inhibition Of Cholinesterasesmentioning

confidence: 99%

“…27,29 The ratio of BuChE:AChE may change from 0.6 to as high as 11.0, 77 which may alter the normally supportive role of BuChE in the hydrolysis of excess ACh. As a dual inhibitor of both AChE and BuChE, rivastigmine may provide maximum preservation of ACh levels independent of the changing contributions of AChE and BuChE to ACh hydrolysis as the disease progresses.…”

Section: Sustained Cholinesterase Inhibition During Long-term Treatmentmentioning

confidence: 99%

“…29 While AChE is present in both diffuse and compact plaques, 94 BuChE becomes associated with the plaques at approximately the same time as β-amyloid protein (Aβ) assumes the neurotoxic compact β-pleated conformation. 95 The association of both AChE and BuChE with Aβ has led to the suggestion that they are actively involved in the malignant transformation of plaques.…”

Section: Potential Effects On Disease Progressionmentioning

confidence: 99%

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Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

304

156

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Background: Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for AChE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy.Objective: The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.Methods: Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine.

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Section: Selectivity For Different Molecular Forms Of Cholinesterasementioning

confidence: 99%

Section: Key Pharmacologic Characteristics Inhibition Of Cholinesterasesmentioning

confidence: 99%

Section: Sustained Cholinesterase Inhibition During Long-term Treatmentmentioning

confidence: 99%

Section: Potential Effects On Disease Progressionmentioning

confidence: 99%

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Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

304

156

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“…This would be consistent with the increased fraction of monomeric AChE-R under stress. Intriguingly, the fraction of AChE monomers increases in Alzheimer's disease (Arendt, Bruckner et al 1992;Ogane) [Giacobini, 2000. Moreover, the therapeutic efficacy of rivastigmine for treating Alzheimer's disease patients has been attributed to its selective interaction with globular monomers of brain AChE, especially in the hippocampus .…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

Soreq¹

2003

PsycEXTRA Dataset

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075REPORT Public reportinq burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing date sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect cif this collection of 'mormaton, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, andtotheOfficeof Vanaqement and Budget, Paperwork Reduction Project (0704-0188) soreq@shum.huji.ac.il SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUPPLEMENTARY NOTESReport contains color graphics. 12a. DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; Distribution unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words)To characterize neuropathological consequences of excess acetylcholinesterase (AChE), we employed transgenic mice developed under previous US Army support. These mice demonstrated association between such excess and adverse responses (in brain and intestine) to pyridostigmine and diisopropylfluorophosphonate. The stress-associated "readthrough" AChE-R variant was seen also in progenitor blood cells, suggesting its use as a surrogate marker for anti-AChE responses. Moreover, AChE-R accumulates in the brain following head injury, its pre-injury excess exacerbates damage, and its antisense suppression improves survival and recovery. Using a 2-hybrid yeast screen we discovered a previously unknown interaction of AChE-R with RACK1, a protein kinase cargo protein involved in signaling processes. Animals carrying a tetracycline-inducible anti-AChE antisense sequence are being characterized for further studies of these interactions. At the extended promoter of the ACHE gene, we found a 4 bp deletion that over-induces transcription and hypersensitivity to pyridostigmine through impairment of HNF3B interaction, and discovered a novel mutation that disrupts the glucocorticoid binding site. Finally, we found AChE-R-specific inhibitor interactions in mouse brain that reflect the specific increase in the AChE-R variant after psychological stress. ( The AChE-R variant thus emerges as the key scavenger and acetylcholine-hydrolyzing agent in several mammalian tissues under various stress insults. Table of contents 3 Introduction 4 Body task 1: characterize the sensory, cognitive and neuromotor consequences of a 5 transgenic excess in AChE variants. task 2: employ transgenic mouse models with up to 300-fold differences in 10 peripheral AChE levels for demonstration of direct correlation between AChE dosage and protection from stress and chemical warfare agents and to test their responses to pyridostigmine administration. task 3: develop RT-PCR tests in peripheral blood cells of model animals, and 12 additional surrogate markers, for follow-up of responses and protection task 5: emplo...

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Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation

1998

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The distribution of the major cholinergic regulatory enzyme acetylcholinesterase (AChE, EC 3.1.1.7) has been extensively studied in the human brain, but the distribution of the closely related enzyme butyrylcholinesterase (BuChE, EC 3.1.1.8) is largely unknown. Because of the importance of BuChE and AChE in Alzheimer's disease, we have studied the distribution of BuChE in the normal human amygdala and hippocampal formation and compared it with that of AChE by using histochemical techniques. In the amygdala, the distribution of BuChE differed significantly from that of AChE in that BuChE was found primarily in neurons and their dendritic processes, whereas AChE was found predominantly in the neuropil. BuChE-positive neurons were present in up to 10% of the neuronal profiles in lateral, basolateral (basal), basomedial (accessory basal), central, cortical, and medial amygdaloid nuclei. AChE was found primarily in the neuropil in these nuclei with only a few AChE-positive neurons. In the hippocampal formation, BuChE was also found in neurons and not in the neuropil, whereas AChE was found in both neurons and in the neuropil. BuChE and AChE neurons were present in the polymorphic layer of the dentate gyrus, as well as the stratum oriens and stratum pyramidale of the hippocampus proper. There was considerable overlap in shapes, sizes, and numbers of BuChE- and AChE-positive neurons, suggesting that the enzymes were colocalized in neurons of the hippocampal formation. The distinct distribution of BuChE suggests that it may have specific functions including coregulation of cholinergic and noncholinergic neurotransmission in human amygdala and hippocampal formation.

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Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development—A study of molecular forms

Cited by 297 publications

References 91 publications

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Genetic and Epigenetic Mechanisms Underlying Acute and Delayed Neurodegenerative Consequences of Stress and Anticholinesterase Exposure

Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation

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