Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

Formaldehyde is endogenously produced in the human body and brain levels of this compound are elevated in neurodegenerative conditions. Although the toxic potential of an excess of formaldehyde has been studied, little is known on the molecular mechanisms underlying its neurotoxicity as well as on the ability of neurons to metabolize formaldehyde. To address these topics, we have used cerebellar granule neuron cultures as model system. These cultures express mRNAs of various enzymes that are involved in formaldehyde metabolism and were remarkably resistant toward acute formaldehyde toxicity. Cerebellar granule neurons metabolized formaldehyde with a rate of around 200 nmol/(h 9 mg) which was accompanied by significant increases in the cellular and extracellular concentrations of formate. In addition, formaldehyde application significantly increased glucose consumption, almost doubled the rate of lactate release from viable neurons and strongly accelerated the export of the antioxidant glutathione. The latter process was completely prevented by inhibition of the known glutathione exporter multidrug resistance protein 1. These data indicate that cerebellar granule neurons are capable of metabolizing formaldehyde and that the neuronal glycolysis and glutathione export are severely affected by the presence of formaldehyde.

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“…, ; Khokhlov et al . cited in Miao and He ), and with oxidative damage and impaired energy metabolism (Haider et al . ; Correia et al .…”

Section: Discussionmentioning

confidence: 99%

Formaldehyde metabolism and formaldehyde‐induced stimulation of lactate production and glutathione export in cultured neurons

Tulpule

Hohnholt

Dringen

2013

Journal of Neurochemistry

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“…Increased expression of formaldehyde‐generating enzymes (Table ) as well as elevated formaldehyde levels have also been reported in brains of patients suffering from neurodegenerative diseases like Alzheimer's disease (AD) or multiple sclerosis (MS) (Khokhlov et al . cited in Miao and He ; Tong et al . , ).…”

Section: Evidence For the Role Of Formaldehyde In Pathologymentioning

confidence: 99%

“…Conditions such as aging and diseases like MS and AD which are associated with increased levels of formaldehyde in brain (Khokhlov et al . cited in Miao and He ; Tong et al . , , b) show impaired mitochondrial function (Sullivan and Brown ; Mahad et al .…”

Section: Formaldehyde‐induced Alterations In Neural Metabolism As Potmentioning

confidence: 99%

Formaldehyde in brain: an overlooked player in neurodegeneration?

Tulpule

Dringen

2013

Journal of Neurochemistry

188

126

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Formaldehyde is an environmental pollutant that is also generated in substantial amounts in the human body during normal metabolism. This aldehyde is a well-established neurotoxin that affects memory, learning, and behavior. In addition, in several pathological conditions, including Alzheimer's disease, an increase in the expression of formaldehydegenerating enzymes and elevated levels of formaldehyde in brain have been reported. This article gives an overview on the current knowledge on the generation and metabolism of formaldehyde in brain cells as well as on formaldehydeinduced alterations in metabolic processes. Brain cells have the potential to generate and to dispose formaldehyde. In culture, both astrocytes and neurons efficiently oxidize formaldehyde to formate which can be exported or further oxidized.Although moderate concentrations of formaldehyde are not acutely toxic for brain cells, exposure to formaldehyde severely affects their metabolism as demonstrated by the formaldehyde-induced acceleration of glycolytic flux and by the rapid multidrug resistance protein 1-mediated export of glutathione from both astrocytes and neurons. These formaldehyde-induced alterations in the metabolism of brain cells may contribute to the impaired cognitive performance observed after formaldehyde exposure and to the neurodegeneration in diseases that are associated with increased formaldehyde levels in brain.

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“…At the same time, FA is also produced endogenously in the body by demethylase and oxidase enzymes that regulate epigenetics , and metabolism , such as lysine-specific demethylase 1 (LSD1), JmjC domain-containing proteins, − and semicarbazide-sensitive amine oxidase . Active degradation by formaldehyde dehydrogenase/ S -nitrosoglutathione reductase and aldehyde dehydrogenase 2 enzymes gives physiological FA levels ranging from 100 μM in blood to 400 μM intracellularly. − Elevations of FA and related RCS are implicated in a variety of disease pathologies, including various cancers, neurodegenerative diseases, ,, diabetes, and chronic liver and heart disorders . The rapidly growing list of modified DNA − and RNA bases, particularly N-methylated bases whose demethylation pathways may involve FA production, − presage a diverse array of important contributions for FA chemistry to biology.…”

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confidence: 99%

An Aza-Cope Reactivity-Based Fluorescent Probe for Imaging Formaldehyde in Living Cells

2015

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Formaldehyde (FA) is a reactive carbonyl species (RCS) produced in living systems that has been implicated in epigenetics as well as in the pathologies of various cancers, diabetes, and heart, liver, and neurodegenerative diseases. Traditional methods for biological FA detection rely on sample destruction and/or extensive processing, resulting in a loss of spatiotemporal information. To help address this technological gap, we present the design, synthesis, and biological evaluation of a fluorescent probe for live-cell FA imaging that relies on a FA-induced aza-Cope rearrangement. Formaldehyde probe-1 (FAP-1) is capable of detecting physiologically relevant concentrations of FA in aqueous buffer and in live cells with high selectivity over potentially competing biological analytes. Moreover, FAP-1 can visualize endogenous FA produced by lysine-specific demethylase 1 in a breast cancer cell model, presaging the potential utility of this chemical approach to probe RCS biology.

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Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

Cited by 6 publications

References 113 publications

Formaldehyde metabolism and formaldehyde‐induced stimulation of lactate production and glutathione export in cultured neurons

Formaldehyde metabolism and formaldehyde‐induced stimulation of lactate production and glutathione export in cultured neurons

Formaldehyde in brain: an overlooked player in neurodegeneration?

An Aza-Cope Reactivity-Based Fluorescent Probe for Imaging Formaldehyde in Living Cells

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