Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Nat Rev Drug Discov. 2020-07-24; 19(9): 609-633
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Cunnane SC(1)(2), Trushina E(3), Morland C(4), Prigione A(5), Casadesus G(6),Andrews ZB(7)(8), Beal MF(9), Bergersen LH(10), Brinton RD(11), de la Monte S(12), Eckert A(13), Harvey J(14)(15), Jeggo R(16), Jhamandas JH(17)(18), Kann O(19), la Cour CM(16), Martin WF(20), Mithieux G(21)(22), Moreira PI(23)(24), Murphy MP(25), Nave KA(26), Nuriel T(27), Oliet SHR(28)(29), Saudou F(30)(31), Mattson MP(32), Swerdlow RH(33), Millan MJ(34).
(1)Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
(2)Research Center on Aging, Sherbrooke, QC, Canada.
(3)Department of Neurology, Mayo Clinic, Rochester, MN, USA.
(4)Department of Pharmaceutical Biosciences, Institute of Pharmacy, University of
Oslo, Oslo, Norway.
(5)Department of General Pediatrics, Neonatology, and Pediatric Cardiology,
University of Dusseldorf, Dusseldorf, Germany.
(6)Department of Biological Sciences, Kent State University, Kent, OH, USA.
(7)Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC,
(8)Department of Physiology, Monash University, Clayton, VIC, Australia.
(9)Department of Neurology, Weill Cornell Medicine, New York, NY, USA.
(10)Department of Anatomy, Institute of Basic Medical Sciences, University of
Oslo, Oslo, Norway.
(11)College of Medicine, University of Arizona, Tucson, AZ, USA.
(12)Brown Medical School, Rhode Island Hospital, Providence, RI, USA.
(13)University of Basel, Basel, Switzerland.
(14)Ninewells Hospital, University of Dundee, Dundee, UK.
(15)Medical School, University of Dundee, Dundee, UK.
(16)Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherche
Servier, Croissy sur Seine, France.
(17)Department of Medicine, University of Albeta, Edmonton, AB, Canada.
(18)Neuroscience and Mental Health Institute, University of Albeta, Edmonton, AB,
(19)Institute of Physiology and Pathophysiology, University of Heidelberg,
(20)Institute of Molecular Evolution, University of Dusseldorf, Dusseldorf,
(21)Lyon Est University, Lyon, France.
(22)INSERM U1213, Lyon, France.
(23)CNC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra,
(24)Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
(25)MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
(26)Department of Biosciences, University of Heidelberg, Heidelberg, Germany.
(27)Columbia University Medical Center, New York, NY, USA.
(28)Neurocentre Magendie, INSERM U1215, Bordeaux, France.
(29)Université de Bordeaux, Bordeaux, France.
(30)University of Grenoble Alpes, Grenoble, France.
(31)INSERM U1216, CHU Grenoble Alpes, Grenoble Institute Neurosciences, Grenoble,
(32)Department of Neuroscience, Johns Hopkins University School of Medicine,
Baltimore, MD, USA.
(33)University of Kansas Alzheimer’s Disease Center, Fairway, KS, USA.
(34)Centre for Therapeutic Innovation in Neuropsychiatry, Institut de Recherche
Servier, Croissy sur Seine, France. .
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.