Formaldehyde in brain: an overlooked player in neurodegeneration?

Abstract 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 formaldehyde‐generating 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 formaldehyde‐induced 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. image The neurotoxin formaldehyde is an environmental pollutant that is also generated during normal brain metabolism. The levels of formaldehyde in brain increase with age and in some neurodegenerative disorders. As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde‐induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders.