The DOI matches its Crossref record; 317 of the 317 references it cites were found in a registry or an index.
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Open accessAbstract
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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“The brain alone consumes 20% of the total energy required by the body, and central nervous system (CNS) mitochondria meet a majority of this massive energy requirement for the brain”
From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Cunnane et al. 2020
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“impaired brain energetics is a core feature across neurodegenerative diseases, including AD, PD, ALS, FTD, and HD.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [574]
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Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
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Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1710504 · Cited by 1,433
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Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023) · Cell · doi:10.1016/j.cell.2022.12.032 · Cited by 1,789
Mitochondrial dysfunction: mechanisms and advances in therapy
Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,382
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
Misrani, A., Tabassum, S., & Yang, L. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.617588 · Cited by 654
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Metadata
- 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
- Published
- 2020-07-24
- Volume
- 19
- Issue
- 9
- Pages
- 609-633
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- 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
- Licence
- 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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