Abnormalities of acetylcholinesterase in Alzheimer's disease with special reference to effect of acetylcholinesterase inhibitor

doi:10.1016/S0166-4328(97)86041-X

Behavioural Brain Research

Volume 83, Issues 1–2, February 1997, Pages 25-30

https://doi.org/10.1016/S0166-4328(97)86041-X Get rights and content

Abstract

In brains from Alzheimer's disease patients, a high activity of acetylcholinesterase (AChE) was detected in the senile plaque-rich fraction and its isozyme pattern was mainly type A, containing a collagen-like tail. AChE inhibitors, including physostigmine, E-2020, amiridin, tetrahydroaminoacridine (THA) and Nicergoline had a poor effect on AChE present in the senile plaque-rich fraction isolated from Alzheimer brain than that either in the soluble fraction of Alzheimer brain or in the control brain. However, AChE purified from rat skeletal muscle (type A) was significantly more susceptible to AChE inhibitors than that purified from rat brain (G4 form) or from human erythrocytes (G2 form). E-2020 inhibited all 3 types of isozymes more effectively than physostigmine, amiridine, Nicergoline or THA. The inhibitory effect of AChE inhibitors on AChE solubilized from senile plaque was also small as compared with AChE in normal human brain, rat brain, human erythrocytes or rat skeletal muscle. These results suggest that the characteristics of AChE present in senile plaques are abnormal or different from that in normal brain or skeletal muscle. As AChE in the Alzheimer brain seems to contain a higher degree of glycosylation, the hydrophobic property of anomalous AChE may serve a seed of amyloid fibril in senile plaques.

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Cited by (29)

The assembly of proline-rich membrane anchor (PRiMA)-linked acetylcholinesterase enzyme: Glycosylation is required for enzymatic activity but not for oligomerization
2011, Journal of Biological Chemistry
Citation Excerpt :
In addition, the accumulation of molecular forms of AChE with an altered pattern of glycosylation has been observed in the brain and cerebrospinal fluid of Alzheimer patients (17). In particular, AChE is associated with the senile plaques and shows a higher degree of glycosylation than in normal tissues (18). Here we analyzed the role of N-glycosylation on the assembly and trafficking of PRiMA-linked G4 AChE.
Acetylcholinesterase (AChE) anchors onto cell membranes by a transmembrane protein PRiMA (proline-rich membrane anchor) as a tetrameric form in vertebrate brain. The assembly of AChE tetramer with PRiMA requires the C-terminal “t-peptide” in AChE catalytic subunit (AChE_T). Although mature AChE is well known N-glycosylated, the role of glycosylation in forming the physiologically active PRiMA-linked AChE tetramer has not been studied. Here, several lines of evidence indicate that the N-linked glycosylation of AChE_T plays a major role for acquisition of AChE full enzymatic activity but does not affect its oligomerization. The expression of the AChE_T mutant, in which all N-glycosylation sites were deleted, together with PRiMA in HEK293T cells produced a glycan-depleted PRiMA-linked AChE tetramer but with a much higher K_m value as compared with the wild type. This glycan-depleted enzyme was assembled in endoplasmic reticulum but was not transported to Golgi apparatus or plasma membrane.
Antisense inhibition at the β-secretase-site of β-amyloid precursor protein reduces cerebral amyloid and acetyl cholinesterase activity in Tg2576
2007, Neuroscience
Citation Excerpt :
An anomalous glycoform of AChE, similar to an isoform seen in AD brain and CSF and which does not bind to Con A, has been reported in Tg2576 mice at 4 and 8 months of age before plaque formation. Fodero et al. (2002); Ulrich et al. (1990); and Mimori et al. (1997) reported that increased AChE was associated with amyloid plaques in human brain. Altered isoforms of AChE have been found increased in AD brain and CSF and co-localized with amyloid plaques (Saez-Valero et al., 2000; Talesa, 2001).
Misprocessing of β-amyloid precursor protein (APP) leading to the formation of elevated quantities of β-amyloid peptide (Aβ), derived by a cleavage at the β-secretase site (N-671/673aa) and by a cleavage at the γ-secretase site (C-711/713aa) of APP, is considered a key event in the pathogenesis of Alzheimer disease (AD). Point mutations near the β-secretase site in the human gene for APP, such as in the Swedish mutation-KM670/671NL, lead to a form of dominantly inherited AD. These mutations are known to promote β-site cleavage and to increase levels of Aβ. Aβ has been shown previously to increase acetyl cholinesterase (AChE) activity in vitro. We wished to test whether translational blocking of APP-mRNA at the mutated β-site by antisense (AS) oligodeoxynucleotides (ODNs) directed to the mutated site will reduce cerebral amyloid in the Swedish transgenic mouse model (Tg2576). Mice were injected i.c.v. with AS-ODNs directed at the mutated β-site (AS-β site) or with AS-ODNs directed at the normal γ-site (AS-γ site) of human APP-mRNA, and compared with procedural controls that received i.c.v. injections of sense ODNs at the β-site (S-β site), sense ODNs at the γ-site (S-γ site) or mismatched ODNs, and with untreated littermates (Lt) and untreated transgenic mice (Tgs). ODNs were injected into the 3rd ventricle once a week for 4 weeks. Brains were processed for enzyme-linked immunosorbent assay analysis of β- and γ-cleaved soluble Aβ40 (sAβ40), β- and γ-cleaved soluble Aβ42 (sAβ42) and α-cleaved soluble β-amyloid precursor protein (sAPPα). The physiological relevance of AS ODNs was tested by evaluating the cerebral distribution of AChE before and after the treatment. AChE was found increased about fivefold in Tg cortex as compared with control brain. Results show that compared with untreated and procedural controls, AS-β increased cerebral levels of sAPPα by 43% and reduced sAβ40/42 by ∼39%; while simultaneously reducing the cortical density of AChE by ∼fourfold in the treated Tg animals, almost to the level found in the control brain (all values P<0.0001, analysis of variance, unpaired two-tailed Student’s t-test), while AS-γ did not have any effect. These results indicate that AS directed to the mutated β-site may be an effective approach to treat familial AD.
Peripheral cholinergic disturbances in Alzheimer's disease
2005, Chemico-Biological Interactions
The most pronounced neurochemical abnormality in Alzheimer's disease (AD) is cholinergic dysfunction in the central nervous system. Peripheral tissues may also be affected, however, including blood. The present study undertook to determine the activity of acetylcholinesterase (AChE) and its molecular forms in erythrocytes, lymphocytes and platelets of normal elderly subjects and probable AD cases. These samples contained dimeric globular (G2), tetrameric globular (G4) and asymmetric (A12) AChE forms, but no globular monomeric (G1) enzyme. In both lymphocytes and platelets, the major AChE molecular form was G2 (approximately 80%), with G4 and A12 forms accounting for nearly equal portions of the remainder. Total AChE activities and measured sedimentation coefficients were similar in the control and AD samples (from patients with mild and moderately severe cognitive deficiency). However, the groups differed significantly in the proportion of certain AChE molecular forms. Thus, as compared with controls, the amount of A12 AChE in the AD samples was increased 148 and 161% in lymphocytes and platelets, respectively. Genotyping for apolipoprotein E (ApoE) and the butyrylcholinesterase K (BCHE-K) variant, carried out using the polymerase chain reaction, showed that AD patients carried the ApoE4 allele at a significantly higher frequency than the controls. On the other hand there were no significant group differences in the occurrence of the BCHE-K variant and no synergism between ApoE alleles and the BCHE-K variant in our Hungarian AD population.
Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease
2004, Medical Hypotheses
Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and non-catalytic actions, unusually strong electrostatics, and exceptionally ubiquitous presence and redundancy in their capacity as the connector, the organizer and the safeguard of the brain, play fundamental role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards, head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile plaques and induce an outside–in cascade of Alzheimer's disease (AD). The alteration in ChEs on the intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary tangles and induce an inside–out cascade of AD. The abnormal patterns of glycosylation and configuration changes in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD.
Brain cholinesterases: III. Future perspectives of AD research and clinical practice
2004, Medical Hypotheses
Alzheimer's disease (AD) is initially and primarily associated with the degeneration and alteration in the metabolism of cholinesterases (ChEs). The use of ChEs inhibitors to treat Alzheimer's condition, on the basis of the cholinergic hypothesis of the disease, is, therefore, without grounds. Most disturbing is the fact that the currently available anti-ChEs are designed to inhibit normal ChEs in the brain and throughout the body, but not the abnormal ones. Based on the acetylcholinesterase (AChE) deficiency theory, treatment should be designed to protect the cranial ChEs system from alteration and/or to help that system fight against degeneration through restoring its homeostatic action for brain structure and function instead. The overlap in the clinical, biochemical, molecular-cellular, and pathological alterations seen in patients with AD and individuals with many other brain disorders, which has bewildered many investigators, may now be explained by the shared underlying mismetabolism of brain ChEs. The abnormal metabolism of ChEs existing in asymptomatic subjects may indicate that the system is “at risk” and deserves serious attention. Future perspectives of ChEs research in vivo and in vitro in connection with AD and clinical diagnosis, prevention and treatment are proposed. Several potentially useful therapeutic and preventive means and pharmacological agents in this regard are identified and discussed, such as physical and intellectual stimulation, and a class of drugs including vitamin E, R-(−)-deprenyl (deprenyl, selegiline), acetyl l-carnitine, cytidine diphosphocholine (CDP-choline), centrophenoxine, l-phenylalanine, naloxone, galactose, and lithium, that have been proven to be able to stimulate AChE activity. Their working mechanisms may be through directly changing the configuration of AChE molecules and/or correcting micro- and overall environmental biological conditions for ChEs.
Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor
2002, Japanese Journal of Pharmacology
A wide range of evidence shows that Cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer’s disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyryl-cholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.

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Research reportAbnormalities of acetylcholinesterase in Alzheimer's disease with special reference to effect of acetylcholinesterase inhibitor

Abstract

Neuroscience

J. Biol. Chem.

J. Biol. Chem.

J. Neurol. Sci.

Lancet

J. Biol. Chem.

Research report
Abnormalities of acetylcholinesterase in Alzheimer's disease with special reference to effect of acetylcholinesterase inhibitor