Frontotemporal Dementia and Glucose Metabolism

Abstract

Frontotemporal dementia (FTD), hallmarked by antero-temporal degeneration in the human brain, is the second most common early onset dementia. FTD is a diverse disease with three main clinical presentations, four different identified proteinopathies and many disease-associated genes. The exact pathophysiology of FTD remains to be elucidated. One common characteristic all forms of FTD share is the dysregulation of glucose metabolism in patients' brains. The brain consumes around 20% of the body's energy supply and predominantly utilizes glucose as a fuel. Glucose metabolism dysregulation could therefore be extremely detrimental for neuronal health. Research into the association between glucose metabolism and dementias has recently gained interest in Alzheimer's disease. FTD also presents with glucose metabolism dysregulation, however, this remains largely an unexplored area. A better understanding of the link between FTD and glucose metabolism may yield further insight into FTD pathophysiology and aid the development of novel therapeutics. Here we review our current understanding of FTD and glucose metabolism in the brain and discuss the evidence of impaired glucose metabolism in FTD. Lastly, we review research potentially suggesting a causal relationship between FTD proteinopathies and impaired glucose metabolism in FTD.

Keywords: C9orf72; C9orf72 ALS/FTD; FTD; FUS; MAPT; TDP-42; glucose.

FIGURE 1

The astrocyte-neuron lactate shuttle (ANLS). Glucose is imported into neurons and astrocytes by their respective transporters, GLUT1 and GLUT3, before being phosphorylated by hexokinase. In neurons most glucose-phosphate is subsequently metabolized along the pentose phosphate pathway, with the early glycolytic enzyme PFKFB3 being inhibited by ubiquitin action. In astrocytes glucose-phosphate is converted into glycogen for storage or metabolized via glycolysis to produce pyruvate, which either enters the mitochondria or is converted into lactate by lactate dehydrogenase (LDH) 5. Lactate is exported by the monocarboxylate transporters (MCT) 1 and 4 and imported into neurons via the MCT 2. It is then converted back to pyruvate via LDH-1 and enters the mitochondrial oxidative phosphorylation cycle. HK, hexokinase; PDHK4, pyruvate dehydrogenase kinase 4; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PDH, pyruvate dehydrogenase; TCAC, tricarboxylic acid cycle; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PPP, pentose phosphate pathway; AcetylCoA, Acetyl coenzyme A. Created with: BioRender.com.

FIGURE 2

Routes of glucose metabolism in cells. Upon entering a cell via a glucose transporter (GLUT) glucose is phosphorylated by hexokinase entrapping glucose-phosphate. This is then metabolized into glycogen (left), along the pentose phosphate pathway (right) or via glycolysis (center). Glycolysis results in the formation of pyruvate which can be interconverted into lactate through the action of lactate dehydrogenase enzymes. Pyruvate can also enter mitochondria, where it is converted into AcetylCoA through the action of pyruvate dehydrogenase which in turn fuels the tricarboxylic acid cycle (TCAC). The TCAC cycle generates NADH and FADH₂ which are required to supply electrons to the electron transport chain (ETC). The ETC generates a proton gradient across the inner mitochondrial membrane, which is used to power the production of ATP by complex V, an ATP synthase. HK, hexokinase; PDHK4, pyruvate dehydrogenase kinase 4; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PDH, pyruvate dehydrogenase; TCAC, tricarboxylic acid cycle; PFKFB3, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3; PPP, pentose phosphate pathway; ETC, electron transport chain; AcetylCoA, Acetyl coenzyme A; NADH, nicotinamide adenine dinucleotide; FADH₂, flavin adenine dinucleotide; ATP, Adenosine triphosphate; ADP, Adenosine diphosphate. Created with: BioRender.com.

FIGURE 3

Impaired glucose metabolism across proteinopathies. Tau, TDP-43, FUS, and FTD-UPS affect various steps of glucose metabolism in neurons and glia, thus impairing the ANLS. The pink cell represents a astrocyte and the light green cell a neuron. HK, hexokinase; PDHK4, pyruvate dehydrogenase kinase 4; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PDH, pyruvate dehydrogenase; TCAC, tricarboxylic acid cycle; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PPP, pentose phosphate pathway; AcetylCoA, Acetyl coenzyme A. Created with: BioRender.com.