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

被引：633

作者：

Cunnane, Stephen C. ^{[1
,2
]}

Trushina, Eugenia ^{[3
]}

Morland, Cecilie ^{[4
]}

Prigione, Alessandro ^{[5
]}

Casadesus, Gemma ^{[6
]}

Andrews, Zane B. ^{[7
,8
]}

Beal, M. Flint ^{[9
]}

Bergersen, Linda H. ^{[10
]}

Brinton, Roberta D. ^{[11
]}

de la Monte, Suzanne ^{[12
]}

Eckert, Anne ^{[13
]}

Harvey, Jenni ^{[14
,15
]}

Jeggo, Ross ^{[16
]}

Jhamandas, Jack H. ^{[17
,18
]}

Kann, Oliver ^{[19
]}

la Cour, Clothide Mannoury ^{[16
]}

Martin, William F. ^{[20
]}

Mithieux, Gilles ^{[21
,22
]}

Moreira, Paula, I ^{[23
,24
]}

Murphy, Michael P. ^{[25
]}

Nave, Klaus-Armin ^{[26
]}

Nuriel, Tal ^{[27
]}

Oliet, Stephane H. R. ^{[28
,29
]}

Saudou, Frederic ^{[30
,31
]}

Mattson, Mark P. ^{[32
]}

Swerdlow, Russell H. ^{[33
]}

Millan, Mark J. ^{[16
]}

机构：

[1] Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada

[2] Res Ctr Aging, Sherbrooke, PQ, Canada

[3] Mayo Clin, Dept Neurol, Rochester, MN USA

[4] Univ Oslo, Inst Pharm, Dept Pharmaceut Biosci, Oslo, Norway

[5] Univ Dusseldorf, Dept Gen Pediat Neonatol Pediat Cardiol, Dusseldorf, Germany

[6] Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA

[7] Monash Univ, Monash Biomed Discovery Inst, Clayton, Vic, Australia

[8] Monash Univ, Dept Physiol, Clayton, Vic, Australia

[9] Weill Cornell Med, Dept Neurol, New York, NY USA

[10] Univ Oslo, Inst Basic Med Sci, Dept Anat, Oslo, Norway

[11] Univ Arizona, Coll Med, Tucson, AZ USA

[12] Rhode Isl Hosp, Brown Med Sch, Providence, RI USA

[13] Univ Basel, Basel, Switzerland

[14] Univ Dundee, Ninewells Hosp, Dundee, Scotland

[15] Univ Dundee, Med Sch, Dundee, Scotland

[16] Inst Rech Servier, Ctr Therapeut Innovat Neuropsychiat, Croissy Sur Seine, France

[17] Univ Albeta, Dept Med, Edmonton, AB, Canada

[18] Univ Albeta, Neurosci & Mental Hlth Inst, Edmonton, AB, Canada

[19] Heidelberg Univ, Inst Physiol & Pathophysiol, Heidelberg, Germany

[20] Univ Dusseldorf, Inst Mol Evolut, Dusseldorf, Germany

[21] Lyon Est Univ, Lyon, France

[22] INSERM U1213, Lyon, France

[23] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, Coimbra, Portugal

[24] Univ Coimbra, Fac Med, Coimbra, Portugal

[25] Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge, England

[26] Heidelberg Univ, Dept Biosci, Heidelberg, Germany

[27] Columbia Univ, Med Ctr, New York, NY USA

[28] Neuroctr Magendie, INSERM U1215, Bordeaux, France

[29] Univ Bordeaux, Bordeaux, France

[30] Univ Grenoble Alpes, Grenoble, France

[31] CHU Grenoble Alpes, Grenoble Inst Neurosci, INSERM U1216, Grenoble, France

[32] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[33] Univ Kansas, Alzheimers Dis Ctr, Fairway, KS USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2020年 / 19卷 / 09期

基金：

欧洲研究理事会; 英国医学研究理事会; 瑞士国家科学基金会; 加拿大健康研究院; 美国国家卫生研究院; 加拿大自然科学与工程研究理事会; 英国惠康基金;

关键词：

TARGETED ANTIOXIDANT MITOQ; MILD COGNITIVE IMPAIRMENT; MITOCHONDRIAL COMPLEX I; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; KETOGENIC DIET; BETA-HYDROXYBUTYRATE; PARKINSONS-DISEASE; GENE-EXPRESSION; DIABETIC-PATIENTS;

D O I：

10.1038/s41573-020-0072-x

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics. 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.

引用

页码：609 / 633

页数：25

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