TY - JOUR
T1 - Brain energy rescue
T2 - an emerging therapeutic concept for neurodegenerative disorders of ageing
AU - Cunnane, Stephen C.
AU - Trushina, Eugenia
AU - Morland, Cecilie
AU - Prigione, Alessandro
AU - Casadesus, Gemma
AU - Andrews, Zane B.
AU - Beal, M. Flint
AU - Bergersen, Linda H.
AU - Brinton, Roberta D.
AU - de la Monte, Suzanne
AU - Eckert, Anne
AU - Harvey, Jenni
AU - Jeggo, Ross
AU - Jhamandas, Jack H.
AU - Kann, Oliver
AU - la Cour, Clothide Mannoury
AU - Martin, William F.
AU - Mithieux, Gilles
AU - Moreira, Paula I.
AU - Murphy, Michael P.
AU - Nave, Klaus Armin
AU - Nuriel, Tal
AU - Oliet, Stéphane H.R.
AU - Saudou, Frédéric
AU - Mattson, Mark P.
AU - Swerdlow, Russell H.
AU - Millan, Mark J.
N1 - Funding Information:
This article is based on the proceedings of a small, focused symposium organized by M.J.M. and supported by an unrestricted grant from Advances in Neuroscience for Medical Innovation, which is affiliated with the Institut de Recherche Servier. S.C.C. is supported by the Alzheimer’s Association (USA), the Canadian Institutes of Health Research, the Fonds de Recherche du Québec – Santé, the Natural Sciences and Engineering Research Council of Canada and Nestlé, and thanks V. St-Pierre, M. Fortier, A. Castellano, É. Myette-Côté, E. Croteau, M. Roy, M.-C. Morin and C. Vandenberghe in particular for outstanding help. M.J.M. thanks J.-M. Rivet for help with preparation of the original graphic artwork and M. Gaillot and her team for the ordering and provision of PDF documents consulted in the preparation of the manuscript. R.H.S. is supported by grants P30 AG035982, R01 AG060733 and R01 AG061194 from the US National Institutes of Health (NIH). E.T. is supported by the NIH National Institute on Aging (grant RF1AG55549) and National Institute of Neurological Disorders and Stroke (grants R01NS107265 and RO1AG062135). Z.B.A. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (APP1154974). P.I.M. is supported by funding from the Alzheimer’s Association (NIRG-13-282387), European Regional Development Fund funds through the operational programme ‘Thematic Factors of Competitiveness’ and by the Portuguese Foundation for Science and Technology (grants PEst-C/SAU/LA0001/2013-2014 and UIDB/04539/2020). G.C. is supported by the NIH (grants 1R15AG050292 and 1R21AG064479). R.D.B. is supported by the National Institute on Aging (grants R37AG053589, R01AG057931 and P01-AG026572). J.H.J. is supported by grants from the Canadian Institutes of Health Research, Alberta Prion Research Institute, the Alzheimer’s Society of Alberta and Northwest Territories and the University Hospital Foundation (Edmonton, AB, Canada). L.H.B. holds grants from Nasjonalforeningen-Demensforbundet, Norway. A.E. is supported by the Swiss National Science Foundation (grant 31003A-179294). O.K. is supported by the Deutsche Forschungsgemeinschaft (grant CRC 1134, B02). M.P.M. is supported by the UK Medical Research Council (MC U105663142) and by a Wellcome Trust Investigator Award (110159/Z/15/Z). F.S. is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (ADG grant agreement no. 834317). W.F.M. is supported by the European Research Council (ADG 666053 and VW 93046). A.P. is supported by the Deutsche Forschungsgemeinschaft (PR1527/5-1) and the German Federal Ministry of Education and Research (AZ.031A318 and 031L0211). K.A.N. is supported by the European Research Council (ADG 671048) and the Adelson Medical Research Foundation. C.M. was supported by the Research Council of Norway: 262647/F20.
Publisher Copyright:
© 2020, Springer Nature Limited.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85088568260&partnerID=8YFLogxK
U2 - 10.1038/s41573-020-0072-x
DO - 10.1038/s41573-020-0072-x
M3 - Review article
C2 - 32709961
AN - SCOPUS:85088568260
SN - 1474-1776
VL - 19
SP - 609
EP - 633
JO - Nature Reviews Drug Discovery
JF - Nature Reviews Drug Discovery
IS - 9
ER -