Acetylcholinesterase Protein Level Is Preserved in the Alzheimer's Brain

Campanari, María-Letizia; García‐Ayllón, María‐Salud; Blázquez-Llorca, Lidia; Luk, Wilson K.W.; Tsim, Karl Wah Keung; Sáez‐Valero, Javier

doi:10.1007/s12031-013-0183-5

Cited by 23 publications

(18 citation statements)

References 87 publications

(98 reference statements)

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“…We also analyzed protein levels of PRiMA-1, the anchorage subunit of the cholinergic G 4 form to the membrane principally expressed in the brain [38, 39]. Similar to a previous report [11], two PRiMA-1 bands of ∼22 and 20 kDa were observed in frontal cortex extracts (Fig. 2D), likely corresponding to mature (fully glycosylated) and immature PRiMA-1 [40].…”

Section: Resultssupporting

confidence: 75%

“…The inactive AChE species are monomers, thought to be synthesized as a reservoir of precursors of enzymatically active tetramers. However, we and others posit that part of inactive pool includes AChE species with specific roles unrelated with cholinergic neurotransmission (discussed in [11]. Increment on inactive AChE-T forms within AD brain may be due in part to alterations on the oligomerization process of tetrameric forms.…”

Section: Discussionmentioning

confidence: 89%

“…However, we recently reported that brain AChE protein levels are unexpectedly similar between AD and non-demented subjects [11]. The discrepancy between AChE activity and protein immunoreactivity levels are attributable, at least in part, to the presence of a large pool of inactive AChE subunits that are relatively spared in the AD brain and cerebrospinal fluid (CSF) [12].…”

Section: Introductionmentioning

confidence: 99%

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Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer’s Disease Patients

Campanari

Navarrete

Ginsberg

et al. 2016

JAD

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Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by Western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR. We found similar protein and mRNA levels of the major cholinergic “tailed”-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic “readthrough” AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by Western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties which are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

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Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer’s Disease Patients

Campanari

Navarrete

Ginsberg

et al. 2016

JAD

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“…Conversely, some authors highlight the importance of measuring AChE levels too, since the two parameters (activity and levels) do not always vary in the same direction [1].…”

Section: Discussionmentioning

confidence: 99%

“…Acetylcholinesterase (AChE) (EC 3.1.1.7) is the enzyme responsible for the termination of cholinergic neurotransmission [1]. Several neurological disorders, chiefly Alzheimer disease (AD), are associated with abnormal expression and activity of this enzyme [2], [3].…”

Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide modifies both activity and isoforms of acetylcholinesterase in human neuroblastoma SH-SY5Y cells

et al. 2017

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The involvement of cholinergic system and the reactive oxygen species (ROS) in the pathogenesis of some degenerative diseases has been widely reported; however, the specific impact of hydrogen peroxide (H2O2) on the acetylcholinesterase (AChE) activity as well as AChE isoform levels has not been clearly established. Hence, the purpose of present study is to clarify whether H2O2 alters these parameters.Human neuroblastoma SH-SY5Y cells were treated with H2O2 (1–1000 µM) for 24 h and AChE activity and AChE and cytochrome c levels were evaluated. AChE activity was strongly increased from 1 µM to 1000 µM of H2O2. The results of the kinetic study showed that H2O2 affected Vmax but not Km; and also that H2O2 changed the sigmoid kinetic observed in control samples to hyperbolic kinetic. Thus, results suggest that H2O2 acts as an allosteric activators. In addition, H2O2, (100–1000 µM) reduced the total AChE content and modified its isoform profile (mainly 50-, 70-, and 132-kDa)·H2O2 from 100 µM to 1000 µM induced cytochrome c release confirming cell death by apoptosis. All these results together suggest: a) the involvement of oxidative stress in the imbalance of AChE; and b) treatment with antioxidant agents may be a suitable strategy to protect cholinergic system alterations promoted by oxidative stress.

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Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

Garcia Ratés,

García‐Ayllón,

Falgàs

et al. 2024

Alzheimer's & Dementia

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This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little‐known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre‐symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p‐Tau and β‐amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of β‐amyloid, and restores cognitive function to that of wild‐type counterparts. Any diagnostic and/or therapeutic strategy based on T14‐NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much‐needed fresh insights into the progression of cell loss underlying AD.Highlights The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early‐stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

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Acetylcholinesterase Protein Level Is Preserved in the Alzheimer's Brain

Cited by 23 publications

References 87 publications

Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer’s Disease Patients

Increased Expression of Readthrough Acetylcholinesterase Variants in the Brains of Alzheimer’s Disease Patients

Hydrogen peroxide modifies both activity and isoforms of acetylcholinesterase in human neuroblastoma SH-SY5Y cells

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

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