Glyceraldehyde metabolism in mouse brain and the entry of blood‐borne glyceraldehyde into the brain

Abstract

D‐Glyceraldehyde, a reactive aldehyde metabolite of fructose and glucose, is neurotoxic in vitro by forming advanced glycation end products (AGEs) with neuronal proteins. In Alzheimer's disease brains, glyceraldehyde‐containing AGEs have been detected intracellularly and in extracellular plaques. However, little information exists on how the brain handles D‐glyceraldehyde metabolically or if glyceraldehyde crosses the blood–brain barrier from the circulation into the brain. We injected [U‐13C]‐D‐glyceraldehyde intravenously into awake mice and analyzed extracts of serum and brain by 13C nuclear magnetic resonance spectroscopy. 13C‐Labeling of brain lactate and glutamate indicated passage of D‐glyceraldehyde from blood to brain and glycolytic and oxidative D‐glyceraldehyde metabolism in brain cells. 13C‐Labeling of serum glucose and lactate through hepatic metabolism of [U‐13C]‐D‐glyceraldehyde could not explain the formation of 13C‐labeled lactate and glutamate in the brain. Cerebral glyceraldehyde dehydrogenase and reductase activities, leading to the formation of D‐glycerate and glycerol, respectively, were 0.27–0.28 nmol/mg/min; triokinase, which phosphorylates D‐glyceraldehyde to D‐glyceraldehyde‐3‐phosphate, has been demonstrated previously at low levels. Thus, D‐glyceraldehyde metabolism toward glycolysis could proceed both through D‐glycerate, glycerol, and D‐glyceraldehyde‐3‐phosphate. The aldehyde group of D‐glyceraldehyde was overwhelmingly hydrated into a diol in aqueous solution, but the diol dehydration rate greatly exceeded glyceraldehyde metabolism and did not restrict it. We conclude that (1) D‐glyceraldehyde crosses the blood–brain barrier, and so blood‐borne glyceraldehyde could contribute to AGE formation in the brain, (2) glyceraldehyde is taken up and metabolized by brain cells. Metabolism thus constitutes a detoxification mechanism for this reactive aldehyde, a mechanism that may be compromised in disease states.image