Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease

Darreh‐Shori, Taher; Vijayaraghavan, Swetha; Aeinehband, Shahin; Piehl, Fredrik; Lindblom, Rickard P F; Nilsson, Bo; Ekdahl, Kristina Nilsson; Långström, Bengt; Almkvist, Ove; Nordberg, Agneta

doi:10.1016/j.neurobiolaging.2013.04.027

Cited by 54 publications

(70 citation statements)

References 66 publications

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“…We found that the secreted levels of IL-6 at 11 DOD of the differentiating neurospheres into the culture medium reached comparable concentrations with the IL-6 levels found in the plasma, but much higher than in CSF of patients with AD [34]. Although such a comparison should be considered with due caution, this suggests that IL-6 might play a role in the regulating mechanisms of stem-cell differentiation, where divergences from the basal physiological secretions could be unfavourable for neurogenesis.…”

Section: Fibrillar Ab Increases Cytokine Secretion From Differentiatimentioning

confidence: 53%

“…The cholinergic signalling molecule ACh has previously been shown to exert immune-regulatory and anti-inflammatory effects [37]. In addition, functional variability in the ACh-degrading capacity of BuChE, which may be induced by various factors, shows a strong relationship with the intrathecal cytokine and astroglial profiles in AD patients [34]. We have also recently shown that hES cells and astrocytes isolated from human brain produce and release the ACh-synthetizing enzyme, ChAT into the culture medium [17].…”

Section: Fibrillar Ab 1-42 Alters the Secretion Of The Ach-regulatingmentioning

confidence: 98%

“…The levels of IL-1b, IFN-c, IL-2, TNF-a and IL-10 secreted from the neurospheres at 11 DOD were considerably lower (ranging from 0.5 to 2.8 pg/ml) than the levels secreted from microglia (ranging from 13.2 to 259.0 pg/ml), with the exception of IL-6 (50.8 pg/ml) that demonstrated similar levels to that secreted from microglia (46.1 pg/ml). Noteworthy, the levels of IL-6 are~35 pg/ml in plasma and 4.5 pg/ml in CSF of patients with AD [34].…”

Section: Differentiating Neurospheres In Culture Exhibit Immunogenic mentioning

confidence: 99%

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Fibrillar β‐amyloid 1‐42 alters cytokine secretion, cholinergic signalling and neuronal differentiation

Malmsten

Vijayaraghavan

Hovatta

et al. 2014

J Cellular Molecular Medi

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Adult neurogenesis is impaired by inflammatory processes, which are linked to altered cholinergic signalling and cognitive decline in Alzheimer's disease. In this study, we investigated how amyloid beta (Aβ)-evoked inflammatory responses affect the generation of new neurons from human embryonic stem (hES) cells and the role of cholinergic signalling in regulating this process. The hES were cultured as neurospheres and exposed to fibrillar and oligomeric Aβ1-42 (Aβf, AβO) or to conditioned medium from human primary microglia activated with either Aβ1-42 or lipopolysaccharide. The neurospheres were differentiated for 29 days in vitro and the resulting neuronal or glial phenotypes were thereafter assessed. Secretion of cytokines and the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and choline acetyltransferase (ChAT) involved in cholinergic signalling was measured in medium throughout the differentiation. We report that differentiating neurospheres released various cytokines, and exposure to Aβf, but not AβO, increased the secretion of IL-6, IL-1β and IL-2. Aβf also influenced the levels of AChE, BuChE and ChAT in favour of a low level of acetylcholine. These changes were linked to an altered secretion pattern of cytokines. A different pattern was observed in microglia activated by Aβf, demonstrating decreased secretion of TNF-α, IL-1β and IL-2 relative to untreated cells. Subsequent exposure of differentiating neurospheres to Aβf or to microglia-conditioned medium decreased neuronal differentiation and increased glial differentiation. We suggest that a basal physiological secretion of cytokines is involved in shaping the differentiation of neurospheres and that Aβf decreases neurogenesis by promoting a microenvironment favouring hypo-cholinergic signalling and gliogenesis.

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Section: Fibrillar Ab Increases Cytokine Secretion From Differentiatimentioning

confidence: 53%

Section: Fibrillar Ab 1-42 Alters the Secretion Of The Ach-regulatingmentioning

confidence: 98%

Section: Differentiating Neurospheres In Culture Exhibit Immunogenic mentioning

confidence: 99%

See 1 more Smart Citation

Fibrillar β‐amyloid 1‐42 alters cytokine secretion, cholinergic signalling and neuronal differentiation

Malmsten

Vijayaraghavan

Hovatta

et al. 2014

J Cellular Molecular Medi

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“…Previous studies have demonstrated human brain esterase activity at the endothelial component of the BBB (Mori et al, 1999;Darreh-Shori et al, 2013), implying that heroin might be hydrolyzed into 6-MAM upon brain entrance. This could explain the rapid increase in 6-MAM brain levels shortly after heroin injection, producing the more potent psychomotor effect compared with injected 6-MAM.…”

Section: Pharmacological Potential Of a Mab Against 6-mammentioning

confidence: 98%

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Kvello¹,

Andersen²,

Øiestad³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Immunotherapy can provide a supplemental treatment strategy against heroin use on the principle of sequestering the active drug in the bloodstream, thereby reducing its distribution to the brain. Previous studies have shown that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the main mediator of acute heroin effects. The objective of the present study was to characterize the pharmacological potential of a monoclonal antibody against 6-MAM (anti-6-MAM mAb) to counteract the heroin response. The individual contributions from heroin and 6-MAM to heroin effects were also examined by pretreating mice with anti-6-MAM mAb (10-100 mg/kg) prior to either heroin or 6-MAM injection (1.25-2.5 mmol/kg). The opioid-induced behavioral response was assessed in a locomotor activity test, followed by opioid and antibody quantification in blood and brain tissue. Pretreatment with mAb caused a profound reduction of heroin-and 6-MAM-induced behavior, accompanied by correspondingly decreased levels of 6-MAM in brain tissue. mAb pretreatment was more efficient against 6-MAM injection than against heroin, leading to an almost complete blockade of 6-MAM-induced effects. mAb pretreatment was unable to block the immediate (5-minute) transport of active metabolites across the blood-brain barrier after heroin injection, indicating that heroin itself appears to enhance the immediate delivery of 6-MAM to the brain. The current study provides additional evidence that 6-MAM sequestration is crucial for counteracting the acute heroin response, and demonstrates the pharmacological potential of immunotherapy against heroin use.

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“…However, many additional genetic influences acting on this pathway are probable, because, for example, the expression of BChE is also cis-regulated from its location on chromosome 2. The suggested role of BChE as a regulator of inflammatory responses is interesting, as we recently identified BChE as a potential regulator of glial activation in Alzheimer disease (52). Recent studies underscore the importance of cholinergic signaling for regulating adaptive immune responses (43), where TNF-a is a key mediating factor (46).…”

Section: Discussionmentioning

confidence: 99%

Unbiased Expression Mapping Identifies a Link between the Complement and Cholinergic Systems in the Rat Central Nervous System

Lindblom

Ström

Heinig

et al. 2014

The Journal of Immunology

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The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA × PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.

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Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease

Cited by 54 publications

References 66 publications

Fibrillar β‐amyloid 1‐42 alters cytokine secretion, cholinergic signalling and neuronal differentiation

Fibrillar β‐amyloid 1‐42 alters cytokine secretion, cholinergic signalling and neuronal differentiation

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

Unbiased Expression Mapping Identifies a Link between the Complement and Cholinergic Systems in the Rat Central Nervous System

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