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.