Abstract
BackgroundFor a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally.The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation.ResultsIn this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions.ConclusionThese observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons.
Highlights
For a long time glucose has been thought to be the main, if not the sole substrate for brain energy metabolism
Specificity of the antibodies Immunohistochemical and Western blot controls clearly showed that monoclonal antibodies against LDH-5 and Pyruvate dehydrogenase (PDH) were specific for lactate dehydrogenase isoenzyme 5 and pyruvate dehydrogenase, respectively
The antibody stained a 43-kDa band from pyruvate dehydrogenase purified from porcine heart and did not stain purified LDH-5 extracted from rabbit muscle
Summary
For a long time glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. In 1988, Fox and Raichle observed by positron emission tomography (PET) a mismatch between glucose uptake and oxygen consumption, raising the possibility that aerobic glycolysis, i.e. the nonoxidative consumption of glucose in the presence of oxygen, may occur in the brain during focal physiologic neural activity [1,2] Further support to this idea was brought by the observation that a lactate peak could be measured during physiological activation by 1H-magnetic resonance spectroscopy (MRS) [3,4]. Since modern imaging techniques such as PET and functional magnetic resonance imaging (fMRI) are being increasingly used for clinical and fundamental biomedical research, it is of interest to understand cellular biochemical events underling observed signals These signals have been shown to result from the interactions between different cerebral cells, raising the concept of "neurovascular unit", including neurons, astrocytes and the vascular endothelium, whereby neuronal activity modulates vascular tension and metabolite delivery from the bloodstream [7]. This ratio is though to be in very close equilibrium with the pyruvate/lactate ratio [14] that depends on glycolysis
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