Cited by 1,003Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsNeurological Disorders and Treatments

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing

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Cunnane, Stephen C., Trushina, Eugenia, Morland, Cecilie, Prigione, Alessandro, Casadesus, Gemma, Andrews, Zane B., Beal, M. Flint, Bergersen, Linda H. +19 more·2020·Nature Reviews Drug Discovery

Abstract

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.

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Authors
Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., Beal, M. F., Bergersen, L. H., Brinton, R. D., de la Monte, S., Eckert, A., Harvey, J., Jeggo, R., Jhamandas, J. H., Kann, O., la Cour, C. M., Martin, W. F., Mithieux, G., Moreira, P. I., Murphy, M. P., Nave, K.-A., Nuriel, T., Oliet, S. H. R., Saudou, F., Mattson, M. P., Swerdlow, R. H., & Millan, M. J.
Affiliations
  • Université de Sherbrooke (CA)
  • Mayo Clinic (US)
  • University of Oslo (NO)
  • Heinrich Heine University Düsseldorf (DE)
  • Monash University (AU)
  • Weill Cornell Medicine (US)
  • University of Arizona (US)
  • University of Basel (CH)
  • University of Dundee (GB)
  • Institut de Recherches Internationales Servier (France) (FR)
  • University of Alberta (CA)
  • Heidelberg University (DE)
  • Inserm (FR)
  • University of Coimbra (PT)
  • University of Cambridge (GB)
  • Columbia University Irving Medical Center (US)
  • Université de Bordeaux (FR)
  • Johns Hopkins University (US)
  • University of Kansas (US)
Corresponding author
  • Cunnane, Stephen C.
  • Millan, Mark J.
Venue
Nature Reviews Drug Discovery
Published
2020-07-24
Volume
19
Issue
9
Pages
609-633
ISSN
  • 1474-1776 (ISSN-L)
  • 1474-1784
OpenAlex
W3044114834
Cited by
1,003
References
317
Citations by year
2026: 174 · 2025: 203 · 2024: 175 · 2023: 174 · 2022: 146 · 2021: 112 · 2020: 19
FWCI
10.79
Type
journal article
Language
en
Open access
Locations
  • Nature Reviews Drug Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
Funders
  • National Science Foundation (P30 AG035982, R37AG053589, R01AG057931)
  • Alzheimer's Association (P30AG035982)
  • Wellcome Trust (110159/Z/ 15/Z, /Z/15/Z)
  • Alzheimer's Society
  • European Commission (PEst-C/SAU/LA0001/2013, HORIZON2020)
  • Deutsche Forschungsgemeinschaft (CRC 1134)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 179294)
  • Servier
  • National Institutes of Health (UIDB/04539/2020, 7r21ag064479-03, 1rf1ag062135-01, AG035982, AG026572)
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council of Canada
  • Fonds de Recherche du Québec - Santé
  • Medical Research Council (MC_UU_00015/3, U105663142, MC-U105663142)
  • National Health and Medical Research Council (1154974)
  • National Institute on Aging (AG026572, RF1AG059093, R21 AG064479, AG035982, RF1-AG062135, P30AG035982, R15AG050292, R01AG061194, RO1AG062135, R01AG057931, RF1AG55549, R01AG060733, RF1AG055549, R37AG053589, P01AG026572)
  • National Institute of Neurological Disorders and Stroke (R01NS107265, UH3NS113776)
  • H2020 European Research Council (834317)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
Keywords
brain energy metabolism, Alzheimer's disease, glucose metabolism, oxidative phosphorylation, aerobic glycolysis, ketone bodies, mitochondrial dysfunction, insulin sensitivity, RNA therapeutics, lifestyle intervention, treatment options
MeSH terms
Aging, Animals, Brain, Energy Metabolism, Glycolysis, Humans, Oxidative Phosphorylation, Neurodegenerative Diseases

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