Cited by 1,003Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsNeuroprotection in Cerebral Ischemia

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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., Brinton, Roberta D., de la Monte, Suzanne, Eckert, Anne, Harvey, Jenni, Jeggo, Ross, Jhamandas, Jack H., Kann, Oliver, la Cour, Clothide Mannoury, Martin, William F., Mithieux, Gilles, Moreira, Paula I., Murphy, Michael P., Nave, Klaus-Armin, Nuriel, Tal, Oliet, Stéphane H. R., Saudou, Frédéric, Mattson, Mark P., Swerdlow, Russell H., Millan, Mark J.·2020·Nature Reviews Drug Discovery

DOI 10.1038/s41573-020-0072-xPMC PMC7948516

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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.
ORCID: Cunnane, Stephen C.
Trushina, Eugenia
Morland, Cecilie
Prigione, Alessandro
Andrews, Zane B.
Bergersen, Linda H.
Brinton, Roberta D.
Eckert, Anne
Harvey, Jenni
Jhamandas, Jack H.
Kann, Oliver
Martin, William F.
Mithieux, Gilles
Moreira, Paula I.
Murphy, Michael P.
Nave, Klaus-Armin
Nuriel, Tal
Oliet, Stéphane H. R.
Saudou, Frédéric
Mattson, Mark P.
Swerdlow, Russell H.
Millan, Mark J.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2020-07-24
Volume: 19
Issue: 9
Pages: 609-633
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/s41573-020-0072-x
PMC: PMC7948516
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: green
discovery.dundee.ac.uk
Licence: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
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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