Brain metabolism in health, aging, and neurodegeneration

Abstract

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.

Keywords: aging; brain energetics; ketone bodies; metabolism.

Figure 1. Nutrient transport across the blood–brain barrier

The blood–brain barrier is formed by capillary endothelial cells surrounded by basement membrane, pericytes, and the astrocyte perivascular end feet. The presence of tight junctions between the endothelial cells strongly inhibits the penetration of water‐soluble molecules. Passive diffusion is limited to gases and small nonpolar lipids. All other nutrients require passive or active mediated transporters. GLUT1‐5, glucose transporter 1‐5; MCT1‐4, monocarboxylic acid transporter 1‐4.

Figure 2. Metabolic pathways of glucose utilization in neurons and astrocytes

In neurons after entering the cell via glucose transporter 3 (GLUT3), glucose is phosphorylated by hexokinase (HK) to glucose‐6‐phosphate (G6P), which is subsequently routed in the glycolytic pathway and the pentose phosphate pathway (PPP). The end product of glycolysis is pyruvate that enters the mitochondria where it is metabolized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation in the electron transport chain (ETC.), generating adenosine‐5′‐triphosphate (ATP) and carbon dioxide (CO2) while consuming oxygen (O2). Pyruvate can also be generated from lactate dehydrogenase 1 (LDH1)‐dependent conversion of lactate. In the PPP, G6P is converted to 6‐phosphogluconate (6PG) that is transformed in ribulose‐5‐phosphate (R5P), with the concomitant production of reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is utilized to regenerate oxidized antioxidants such as glutathione (GSH) and thioredoxin. Neurons are not able to store glucose in the form of glycogen due to constitutive degradation of glycogen synthase (GS) via glycogen synthase kinase 3 (GSK3) phosphorylation, and subsequent ubiquitin‐dependent proteasomal digestion mediated by the malin–laforin complex. In astrocytes, glucose is imported trough glucose transporter 1 (GLUT1) and preferentially stored as glycogen, or metabolized via glycolysis. The pyruvate generated is converted to lactate thanks to the expression of lactate dehydrogenase 5 (LDH5), and pyruvate dehydrogenase kinase 4 (PDK4)‐dependent inhibition of pyruvate dehydrogenase (PDH). The presence of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (Pfkfb3) allows astrocytes to generate fructose‐2,6‐bisphosphate (F2,6P) that acts as an allosteric modulator of PKF1 boosting glycolysis. Abbreviations are as follows: F6P, fructose‐6‐phosphate; PKF1, phosphofructokinase 1; F1,6P, fructose‐1,6‐diphosphate; G3P, glyceraldehyde‐3‐phosphate; Mit, mitochondrion; PEP, phosphoenolpyruvate; PKM1, pyruvate kinase M1; PKM2, pyruvate kinase M2; G1P, glucose‐1‐phosphate; GP, glycogen phosphorylase; APC/C‐Cdh1, anaphase‐promoting complex C/cytosome‐Cdh1; MCT, monocarboxylic acid transporter.

Figure 3. Schematic of ketone body oxidative and anabolic utilization in brain

Under conditions of reduced glucose availability such as low carbohydrates/high‐fat diet, exercise, or fasting, the liver utilizes fatty acids mobilized from adipose tissue and ketogenic amino acids (i.e. leucine, lysine, phenylalanine, isoleucine, tryptophan, tyrosine, threonine) to produce acetoacetate (AcAc), 3‐β‐hydroxybutyrate (3HB), and acetone (Ac). Acetone is considered to have negligible metabolic significance and rapidly eliminated through urine and lungs. Ketone bodies cross the blood–brain barrier via monocarboxylate transporters (MCTs). Inside the cells, they may be directed toward anabolic or oxidative pathways depending on the developmental stage and cellular requirements. In the anabolic pathway taking place in the cytosol, acetoacetate is converted into acetoacetyl‐CoA (AcAc‐CoA) by acetoacetyl‐CoA synthase (AACS). AcAc‐CoA can be condensed with acetyl‐CoA to generate the precursor of sterols, 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) by 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 1 (HMGCS1). The acetyl‐CoA produced from AcAc‐CoA by cytosolic β‐ketothiolase (cBKD), or from citrate by ATP‐citrate lyase (ACLY), can be transformed in malonyl‐CoA for fatty acid synthesis. Amino acid can be synthesized utilizing intermediates of the TCA cycle. Oxidation of ketones occurs in the mitochondria (Mit) where AcAc directly taken up or generated from 3HB by 3‐β‐hydroxybutyrate dehydrogenase (BDH) is transformed into acetyl‐CoA via succinyl‐CoA‐3‐oxoacid CoA transferase (SCOT), and mitochondrial β‐ketothiolase (mBKD). The complete oxidation of AcAc yields 23 molecules of ATP, while 3HB generates 26 molecules of ATP.

Figure 4. Age‐related cognitive decline as a result of neuroanatomical changes driven by decreased energy supply

The neuronal firing patterns that play an important role in normal cognitive processing rely on the neurons' ability to exchange information across synapses. Compared to young neurons (left), aging neurons (right) are characterized by a significant reduction of the dendritic tree, as well as changes in spines size, shape, density, and turnover. Age‐dependent diminished nutrient import, as well as changes in glycolytic and oxidative phosphorylation efficiency, results in decreased ATP production. The reduced energy availability impairs the ability of aging neurons to preserve synapse homeostasis. The resulting structural changes lead to perturbations in neuronal function, and impairments in memory and learning.

Figure 5. Signaling pathways mediating adaptive responses of neurons to bioenergetic challenges

Exercise and fasting affect subcellular processes in neurons by brain‐intrinsic mechanisms mediated by increased neuronal network activity, and via signals coming from the periphery including 3‐β‐hydroxybutyrate (3HB), cathepsin B, and irisin. Intellectual challenges involve increased neuronal network activity and consequent activation of calcium‐responsive pathways. BDNF expression is up‐regulated by neuronal network activity, as well as 3HB, cathepsin B, and irisin, and BDNF is known to mediate, at least in part, the enhancement of neuronal plasticity and stress resistance by exercise, fasting, and intellectual challenges. Exercise, fasting, and intellectual challenges result in the activation of glutamate receptors at excitatory synapses, Ca²⁺ influx, and activation of Ca²⁺ calmodulin‐dependent protein kinase (CaMK) which, in turn, activates the transcription factor cyclic AMP response element‐binding protein (CREB). CREB can directly and indirectly modulate mitochondrial biogenesis via expression of several genes (i.e. BDNF, PGC‐1α, NRF1, PPARα, and TFAM). Activation of glutamate receptors also induces the expression of the mitochondrial protein sirtuin 3 (SIRT3) which can protect neurons by deacetylating superoxide dismutase 2 (SOD2) to increase its enzymatic activity, and thus reduce mitochondrial oxidative stress, and by inhibiting cyclophilin D (CycD), a protein involved in the formation of membrane permeability transition pores (PTP). 3‐β‐Hydroxybutyrate (3HB) can induce BDNF expression in neurons via the Ca²⁺–CREB pathway, and a pathway involving mitochondrial reactive oxygen species (ROS) and activation of the transcription factor nuclear factor κB (NF‐κB). BDNF is released from neurons and activates the receptor tropomyosin receptor kinase B (TrkB), on the same neuron and adjacent neurons, engaging downstream intracellular pathways which activate transcription factors that induce the expression of genes encoding proteins involved in synaptic plasticity, learning and memory, and neuronal stress resistance. Abbreviations are as follows: Pgc1a, peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha; NRF1, nuclear regulatory factor 1; PPARα, peroxisome proliferator‐activated receptor α; TFAM, mitochondrial transcription factor A; GLUT3, glucose transporter 3; MCT2, monocarboxylic acid transporter 2; PI3K, phosphoinositide 3 kinase; Akt, protein kinase B; ERK, extracellular signal regulated kinase; ETC., electron transport chain; ATP, adenosine‐5′‐triphosphate; APE1, apurinic/apyrimidinic endonuclease 1.