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.

Fig. 1 |. Energy supply and use by neurons and other brain cells.

a | Organization of the neurovascular unit, which functions to supply glucose (Glc) to neurons. b | Astrocytes produce ATP mainly via aerobic glycolysis (glucose to pyruvate (Pyr)), yet also exploit oxidative phosphorylation in mitochondria (ovals) to generate ATP using the tricarboxylic acid (TCA) cycle. Astrocytes supply glucose to neurons and oligodendrocytes from capillaries and endogenous stores of glycogen, a reversible transformation. Astrocytes take up glutamate (Glu) released from synapses and convert it into glutamine (Gln), which is sent to neurons: this metabolically costly operation relieves neurons of an energetic burden. Some glutamate and glutamine contributes carbon to the TCA cycle via the intermediate α-ketoglutarate (α-KG). Astrocytic generation of ketones from acetyl coenzyme A (acetyl-CoA) and uptake of lactate (Lac) and medium-chain fatty acids is not shown for clarity. c | Oligodendrocytes insulate axons with myelin and deliver lactate to axons, which is transformed into pyruvate and then ATP by mitochondria. Axons promote their own energy supply by releasing glutamate to stimulate N-methyl-d-aspartate receptors (NMDARs) on oligodendrocytes; this promotes membrane insertion of GLUT1 and increased oligodendrocyte uptake of glucose delivered as lactate to axons. d | Microglia support neurons by clearing pathogens, waste and toxic proteins but do not provide them with energy. They generate ATP mainly from glucose but also from free fatty acids and glutamine. Fatty acid and fructose (prominent in ‘modern diets’) uptake by microglia is linked to neuroinflammation in neurodegenerative disorders of ageing. e | Neurons use transporters to acquire glucose and lactate from astrocytes or the vasculature. Food, adipose tissue and gut microbiota yield short-chain fatty acids (SCFAs) and triglycerides (TGs), which are transformed by the liver into the ketones d-β-hydroxybutyrate (BHB) and acetoacetate (AcAc), which are taken up by neurons. Glucose enters the TCA cycle via pyruvate and acetyl coenzyme A to yield ATP or the pentose phosphate pathway to provide (via glucose 6-phosphate (G6P)) the antioxidant glutathione (GSH) and nucleosides. Neurons also generate some ATP by aerobic glycolysis. Microtubule transport of mitochondria and other cargo is driven by ATP, partially generated by ‘onboard’ glycolytic enzymes. See the main text and Supplementary Fig. 1 for details. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; EAAT, excitatory amino acid transporter; FABP, fatty acid-binding protein; FFA, free fatty acid; GLUT, glucose transporter; HK, hexokinase; LDH, lactate dehydrogenase; LPL, lipoprotein lipase; MCT, monocarboxylate transporter; mGluR, metabotropic glutamate receptor; Rib5P, ribonucleoside 5-phosphate; SLC1A5, solute carrier family 1 member 5; SLC38A1, solute carrier family 38 member 1; SNAT, sodium-coupled neutral amino acid transporter.

Fig. 2 |. Causes and consequences of the brain energy gap in neurodegenerative disorders.

a | Brain glucose hypometabolism occurs in conditions that increase the risk of Alzheimer disease (AD). The persistent brain energy gap and the neuropathological processes both contribute to a vicious cycle leading to brain energy exhaustion and dysfunction. Brain energy rescue strategies (FIG. 3; TABLES 1–3) attempt to inhibit the positive feedback between the brain energy gap and neuropathology involving amyloid-β and phosphorylated tau (dashed black arrow). Hormones (principally insulin, adipokines and incretins), as well as synthetic agonists and insulin sensitizers, can influence brain energy rescue and inhibit the onset of neuropathology. b | Glucose contributes to about 95% of total brain fuel supply in cognitively healthy young adults, and ketones supply the remaining 5%. In cognitively healthy older adults, brain glucose uptake is decreased by about 9%, in people with mild cognitive impairment (MCI) it is decreased by about 12% and in people with mild-to-moderate AD it is decreased by about 18%. The magnitude of the brain energy gap is the difference in total brain fuel uptake (glucose and ketones combined) between healthy young adults and people with mild-to-moderate AD; that is, the therapeutic target for brain energy rescue in MCI and AD. The brain energy gap has not been rigorously quantified in neurodegenerative disorders of ageing other than AD.

Fig. 3 |. Brain energy disruption and rescue strategies.

a | Several pathways of brain energy metabolism in neurons are disrupted (shown with dashed black arrows) in neurodegenerative disorders of ageing (specific disorders with declines are shown in the red boxes). Increased production of reactive oxygen species (ROS) and neuroinflammation that negatively affect brain energy levels are shown with a thick black arrow. The combination of impaired ATP production and increased levels of ROS contributes to declining brain function. b | Molecules or potential therapies implicated in brain energy rescue strategies target six broad pathways: ATP and redox state (light blue); brain glucose transport and/or aerobic glycolysis (dark blue; interventions indicated with an asterisk: adiponectin, ghrelin, insulin (GLUT4 only), nicotinamide riboside, dichloroacetate, N-acetylcysteine, oxaloacetate, glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic polypeptide (GIP), leptin, amylin, metformin, liraglutide and sitagliptin); anaplerosis and the tricarboxylic acid (TCA) cycle (purple; propionic acid (C3), heptanoic acid (C7), octanoic acid (C8), d-β-hydroxybutyrate (BHB), and ketone esters (KE)); mitochondrial transport and biogenesis (olive-grey); ketogenesis (orange; interventions indicated with two asterisks: BHB, C8, decanoic acid (C10) and KE); or protection against ROS and inflammation (light green; interventions indicated with three asterisks: ghrelin, GLP1, GIP, leptin, adiponectin, metformin, AP39, mitochondrial division inhibitor 1 (mdivi-1), MitoQ, BHB, ketogenic diet and KE). Details of the molecules or potential therapies are shown in TABLE 1 (preclinical studies) and TABLES 2,3 (clinical studies). Complementary interventions such as caloric restriction, ketogenic diet and exercise are not shown. Neurons take up lactate generated by astrocytes and oligodendrocytes (not shown). Medium-chain fatty acids such as decanoic acid and octanoic acid in the circulation can enter astrocytes and produce ketones and acetyl coenzyme A (acetyl-CoA). AAV, adeno-associated virus; AcAc, acetoacetate; acetyl-CoA, acetyl coenzyme A; Ach, acetylcholine; AD, Alzheimer disease; AG, aerobic glycolysis; ALS, amyotrophic lateral sclerosis; ApoE4, E4 isoform of apolipoprotein E; ASO, antisense oligonucleotide; ATP Syn, ATP synthase; DA1, dynamin-related protein antagonist 1; ETC, electron transport chain; FTD, frontotemporal dementia; HD, Huntington disease; MCT, monocarboxylate transporter; mHTT, mutant huntington protein; NR, nicotinamide riboside; PD, Parkinson disease; PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1α; PDH, pyruvate dehydrogenase; PPP, pentose phosphate pathway.