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

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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Fig. 1: Energy supply and use by neurons and other brain cells.
Fig. 2: Causes and consequences of the brain energy gap in neurodegenerative disorders.
Fig. 3: Brain energy disruption and rescue strategies.

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Acknowledgements

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.

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Correspondence to Stephen C. Cunnane or Mark J. Millan.

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Competing interests

S.C.C. declares that he has consulted for and has received honoraria, test products and/or research funding from Abitec, Accera, Bulletproof, Nestlé and Servier, is the founder of Senotec and is co-inventor on a patent for a medium chain triglyceride formulation. M.J.M. declares that he is a full-time employee of Servier and has no other interests to declare. M.P.M. declares that he holds patents related to therapies targeted at decreasing oxidative damage to mitochondria. G.C. declares that she holds a patent related to compositions and methods for treating cognitive deficits using amylin and other hormones. A.E. declares that she has received honoraria, test products and/or research funding from Schwabe and Vifor. F.S. declares that he has consulted for Servier and TEVA. R.D.B. declares that she holds patents for therapeutics targeting Alzheimer disease and neurodegenerative disorders of ageing and is the founder of NeuTherapeutics. E.T. declares that she holds a patent related to compositions and methods for treating cognitive deficit using complex I inhibitors. All other authors declare no competing interests.

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Glossary

Neuroinflammation

An inflammatory response or state in the brain that involves functional, morphological and energetic shifts in microglia and ‘reactive’ astrocytes, as well as macrophages that migrate into the brain from the periphery. It is a characteristic of neurodegenerative disorders and brain response to infectious agents or injury.

Ketone bodies

(Ketones). β-Hydroxybutyrate and acetoacetate. Produced endogenously by fatty acid β-oxidation during caloric or severe carbohydrate restriction, and from medium-chain fatty acids. Exogenous ketones are mostly salts or esters of β-hydroxybutyrate. Acetone is a breakdown product of acetoacetate that is measurable in plasma and on breath.

Microglia

Resident brain macrophages of mesodermal origin that clear neurotoxic proteins and protect neurons from damaging exogenous molecules, toxins, infectious agents or pathogens. Excess and persistent microglial activation is associated with neuroinflammation, neuronal energetic deterioration and progression of neurodegenerative diseases of ageing.

Oligodendrocytes

Cells that produce myelin to insulate the axon and increase the speed of action potential propagation. They energetically support and communicate with neurons and astrocytes.

Neurovascular coupling

Coordinated response to brain activation involving local capillary dilation and a transitory surge in the flow of oxygenated, glucose-containing blood across the neurovascular unit, thereby replenishing ATP used in neurotransmission.

Insulin resistance

A state in which insulin is ineffective in stimulating glucose use by peripheral tissues and certain populations of neurons in the brain, due mainly to receptor-signalling desensitization. It is associated with glucose intolerance and type 2 diabetes, and increases the risk of neurodegenerative disorders, particularly Alzheimer disease.

Oxidative phosphorylation

Process by which mitochondria generate ATP by conveying electrons through enzyme complexes (I to IV), thereby creating a proton gradient that powers phosphorylation of ADP to ATP by ATP synthase.

Tricarboxylic acid cycle

(TCA cycle). Process by which acetyl coenzyme A is oxidized to form GTP, FADH2 and NADH. NADH and FADH2 feed electrons to the electron transport chain to produce ATP by oxidative phosphorylation. Several neurotransmitters (acetylcholine, glutamate and GABA) are produced by carbon leaving the TCA cycle.

Aerobic glycolysis

Conversion of glucose into pyruvate by the Emden–Meyerhoff pathway. Pyruvate is either converted into acetyl coenzyme A and enters the TCA cycle or reduced to lactate by NADH, a pathway prominent in glia to produce ATP without oxygen. Aerobic glycolysis may also occur in neurons.

Astrocyte–neuron lactate shuttle

The hypothesis that lactate produced in astrocytes is delivered to neurons to support the energy requirements of neurotransmission.

Fast axonal transport

Rapid transport of vesicles, mitochondria and other cargo along axonal microtubules. Vesicles are equipped with molecular motors (kinesin and dynein) and glycolytic enzymes, permitting rapid, local ATP production by aerobic glycolysis.

Incretins

Peptide hormones produced by the small intestine that stimulate pancreatic insulin secretion, regulate glucose metabolism and influence cognition. These include glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide.

Monocarboxylate transporters

Transporters in the cell membrane that facilitate unidirectional, proton-linked transport (uptake) of small monocarboxylic acids such as lactate and ketones.

Short-chain fatty acids

Acetate (two carbons), propionate (three carbons) and butyrate (four carbons). End products of microbial fermentation of dietary polysaccharides (soluble fibre). Butyrate is ketogenic and propionate is anaplerotic.

Cataplerosis

Process by which intermediates (carbon) leave the tricarboxylic acid cycle to support biochemical reactions; that is, acetylcholine and lipid synthesis from citrate, or amino acid synthesis from α-ketoglutarate and oxaloacetate; opposite of anaplerosis.

Mild cognitive impairment

(MCI). A condition prodromal to Alzheimer disease that is characterized by a subjective memory impairment and modest deficits in at least one of five main cognitive domains (executive function, memory, language, processing speed or attention). About 50% of cases progress to Alzheimer disease within 5 years.

Cerebral metabolic rate

Quantity of energy substrate consumed by the brain (micromoles per 100 g per minute). Typically refers to glucose, but also used for brain consumption of oxygen, lactate and ketones.

Brain energy gap

Deficit in brain energy metabolism of about 10% in mild cognitive impairment and of about 20% in early Alzheimer disease. Also present in other neurodegenerative disorders of ageing. It appears to be specific to glucose inasmuch as no studies to date have shown that brain ketone metabolism is affected.

Caloric restriction

Limiting food intake to a level that does not permit full satiety. Can be self-determined (usually the case in human studies) or imposed relative to the food consumed by a matched group fed ad libitum (usually only in animal studies).

Electron transport chain

A series of enzymatic protein complexes in the inner mitochondrial membrane that transfer electrons donated from NADH (complex I) or fatty acid dehydrogenase (complex II) to oxygen (complex IV).

Medium-chain triglycerides

Edible oils comprising saturated fatty acids of 6–14 carbons in length. These have long been used in clinical nutrition to support energy needs in diseases or conditions involving malabsorption. Eight-carbon medium-chain triglycerides are more ketogenic than those of 10 or 12 carbons.

Mitochondrial biogenesis

Renewal of mitochondria. In neurons, mitochondrial biogenesis occurs in the cell body with newly formed mitochondria being transported along the axon to dendritic synapses.

Redox state

Capacity of a molecule to be reduced or acquire electrons; opposite of oxidation. Many biological reactions involve the reduction of one molecular species while another is being simultaneously oxidized. Energy metabolism is highly dependent on the redox state of the cell.

Ketogenic diet

A very-low-carbohydrate, very-high-fat diet inciting the liver to produce ketones from free fatty acids released from adipose tissue because there is minimal insulin production. The stricter, medical form of the ketogenic diet developed to treat intractable epilepsy usually also limits dietary protein.

Anaplerosis

Process by which four-carbon or five-carbon units enter the tricarboxylic acid cycle independently of acetyl coenzyme A to replenish intermediates used in the synthesis of acetylcholine or lipids (from citrate) or amino acids (from α-ketoglutarate and oxaloacetate); opposite of cataplerosis.

Antagomirs

Also known as anti-microRNAs or blockmirs. Synthetic oligonucleotides engineered to silence endogenous microRNAs or prevent other molecules from binding to a specific mRNA.

Locked nucleic acids

RNAs in which the flexibility of the ribose ring has been restrained by adding a methylene bridge connecting the 2′ oxygen and 4′ carbon. Oligonucleotides containing locked nucleic acids have increased specificity, sensitivity and hybridization stability.

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Cunnane, S.C., Trushina, E., Morland, C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov 19, 609–633 (2020). https://doi.org/10.1038/s41573-020-0072-x

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