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Brain aerobic glycolysis functions and Alzheimer’s disease

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Abstract

Genetic, biochemical, pathological, and biomarker data demonstrate that Alzheimer’s disease (AD) pathology, including the initiation and progressive buildup of insoluble forms of beta-amyloid (Aβ), appears to begin ~10–15 years prior to the onset of cognitive decline associated with AD. Metabolic dysfunction, a prominent feature of the evolving brain pathology, is reflected in a decline of total glucose utilization. Despite decades of interest in declining glucose use in AD no detailed consideration had been given to the possibility that this decline is not just a decline in energy consumption but rather in glycolysis alone. Glycolysis is a multi-step process that prepares the glucose molecule for oxidative phosphorylation and the generation of energy. In the normal brain, glycolysis exceeds that required for the needs of oxidative phosphorylation. Because it is occurring in a setting with adequate oxygen available for oxidative phosphorylation it is often referred to as aerobic glycolysis (AG). AG is a biomarker of a group of metabolic functions broadly supporting biosynthesis and neuroprotection. The distribution of AG in normal young adults correlates spatially with Aβ deposition in AD patients and cognitively normal individuals with elevated Aβ. In transgenic mice extracellular fluid Aβ and lactate, a marker of AG, vary in parallel regionally and with changes in activity. Reducing neuronal activity locally in transgenic mice attenuates plaque formation suggesting that plaque formation is an activity-dependent process associated with aerobic glycolysis.

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Conflict of interest

The authors, Andrei G. Vlassenko, MD, PhD, and Marcus E. Raichle, MD declare no conflict of interest regarding this article.

Human and animal studies

For studies previously published by the authors all institutional and national guidelines for the care and use of laboratory animals were followed; human studies were approved by the Human Research Protection Office and Radioactive Drug Research Committee, and written informed consent was provided by all participants or their caregivers.

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  1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott Ave East Building, Campus Box 8225, St. Louis, MO, 63110, USA

    Andrei G. Vlassenko

  2. Mallinckrodt institute of Radiology, Washington University School of Medicine, 4525, Scott Avenue, East Building, Rm 2116, St Louis, MO, 63110, USA

    Marcus E. Raichle

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Correspondence to Andrei G. Vlassenko.

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Vlassenko, A.G., Raichle, M.E. Brain aerobic glycolysis functions and Alzheimer’s disease. Clin Transl Imaging 3, 27–37 (2015). https://doi.org/10.1007/s40336-014-0094-7

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  • DOI: https://doi.org/10.1007/s40336-014-0094-7

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