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

Stephen C. Cunnane; Eugenia Trushina; Cecilie Morland; Alessandro Prigione; Gemma Casadesus; Zane B. Andrews; M. Flint Beal; Linda H. Bergersen; Roberta D. Brinton; Suzanne de la Monte; Anne Eckert; Jenni Harvey; Ross Jeggo; Jack H. Jhamandas; Oliver Kann; Clothide Mannoury la Cour; William F. Martin; Gilles Mithieux; Paula I. Moreira; Michael P. Murphy; Klaus-Armin  Nave; Tal Nuriel; Stéphane H. R. Oliet; Frédéric Saudou; Mark P. Mattson; Russell H. Swerdlow; Mark J. Millan

doi:10.1038/s41573-020-0072-x

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

Stephen C. Cunnane (Lead / Corresponding author), Eugenia Trushina, Cecilie Morland, Alessandro Prigione, Gemma Casadesus, Zane B. Andrews, M. Flint Beal, Linda H. Bergersen, Roberta D. Brinton, Suzanne de la Monte, Anne Eckert, Jenni Harvey, Ross Jeggo, Jack H. Jhamandas, Oliver Kann, Clothide Mannoury la Cour, William F. Martin, Gilles Mithieux, Paula I. Moreira, Michael P. MurphyKlaus-Armin Nave, Tal Nuriel, Stéphane H. R. Oliet, Frédéric Saudou, Mark P. Mattson, Russell H. Swerdlow, Mark J. Millan (Lead / Corresponding author)

Research output: Contribution to journal › Review article › peer-review

498 Citations (Scopus)

634 Downloads (Pure)

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.

Original language	English
Pages (from-to)	609-633
Number of pages	25
Journal	Nature Reviews Drug Discovery
Volume	19
Issue number	9
Early online date	24 Jul 2020
DOIs	https://doi.org/10.1038/s41573-020-0072-x
Publication status	Published - 1 Sept 2020

Keywords

Alzheimer's disease
Drug development
Outcomes research

ASJC Scopus subject areas

Drug Discovery
Pharmacology

Access to Document

10.1038/s41573-020-0072-x

Author Accepted ManuscriptAccepted author manuscript, 756 KB

Cite this

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., Mannoury la Cour, C., Martin, W. F., Mithieux, G., Moreira, P. I., ... Millan, M. J. (2020). Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nature Reviews Drug Discovery, 19(9), 609-633. https://doi.org/10.1038/s41573-020-0072-x

@article{43772bffb6554ab58ac8243d4f9501b8,

title = "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.",

keywords = "Alzheimer's disease, Drug development, Outcomes research",

author = "Cunnane, {Stephen C.} and Eugenia Trushina and Cecilie Morland and Alessandro Prigione and Gemma Casadesus and Andrews, {Zane B.} and Beal, {M. Flint} and Bergersen, {Linda H.} and Brinton, {Roberta D.} and {de la Monte}, Suzanne and Anne Eckert and Jenni Harvey and Ross Jeggo and Jhamandas, {Jack H.} and Oliver Kann and {Mannoury la Cour}, Clothide and Martin, {William F.} and Gilles Mithieux and Moreira, {Paula I.} and Murphy, {Michael P.} and Klaus-Armin Nave and Tal Nuriel and Oliet, {St{\'e}phane H. R.} and Fr{\'e}d{\'e}ric Saudou and Mattson, {Mark P.} and Swerdlow, {Russell H.} and Millan, {Mark J.}",

year = "2020",

month = sep,

day = "1",

doi = "10.1038/s41573-020-0072-x",

language = "English",

volume = "19",

pages = "609--633",

journal = "Nature Reviews Drug Discovery",

issn = "1474-1776",

publisher = "Nature Publishing Group",

number = "9",

}

Cunnane, SC, Trushina, E, Morland, C, Prigione, A, Casadesus, G, Andrews, ZB, Beal, MF, Bergersen, LH, Brinton, RD, de la Monte, S, Eckert, A, Harvey, J, Jeggo, R, Jhamandas, JH, Kann, O, Mannoury la Cour, C, Martin, WF, Mithieux, G, Moreira, PI, Murphy, MP, Nave, K-A, Nuriel, T, Oliet, SHR, Saudou, F, Mattson, MP, Swerdlow, RH & Millan, MJ 2020, 'Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing', Nature Reviews Drug Discovery, vol. 19, no. 9, pp. 609-633. https://doi.org/10.1038/s41573-020-0072-x

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 - Mannoury la Cour, Clothide

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.

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.

KW - Alzheimer's disease

KW - Drug development

KW - Outcomes research

UR - http://www.scopus.com/inward/record.url?scp=85088568260&partnerID=8YFLogxK

U2 - 10.1038/s41573-020-0072-x

DO - 10.1038/s41573-020-0072-x

M3 - Review article

C2 - 32709961

SN - 1474-1776

VL - 19

SP - 609

EP - 633

JO - Nature Reviews Drug Discovery

JF - Nature Reviews Drug Discovery

IS - 9

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Harvey, Jenni

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Profiles

Harvey, Jenni

Cite this