Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro

Abstract

Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer’s disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [14C]fructose or its AGE-prone metabolite [14C]glyceraldehyde into rat neocortex in vivo led to formation of 14C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [14C]fructose labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. Hexokinase 1, which channels fructose into glycolysis, was highly expressed, and enzyme activity was similar with fructose or glucose as substrates, whereas the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only ~4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. Fructose may be formed from glucose through the polyol pathway. The genes encoding enzymes of this pathway, aldose reductase and sorbitol dehydrogenase, were expressed in rat neocortex. We conclude that fructose is transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity.

Specific regions of the brain are capable of fructose metabolism

“…While recent studies have reported fructose metabolism in some regions of the brain that express khk (including the eye, cortex, and the rostral ventrolateral medulla) (Hassel et al, 2015; Meakin et al, 2007; Wu et al, 2014), this study reveals a more pervasive capacity for multiple brain regions for fructose metabolism. Furthermore, these studies revealed for the first time that KHK activity in the mouse brain increased on a high fructose diet.…”

Glyceraldehyde caused Alzheimer’s disease-like alterations in diagnostic marker levels in SH-SY5Y human neuroblastoma cells

“…Fructose is phosphorylated to fructose-1-phosphate and then catabolized to dihydroxyacetone phosphate and GA by liver aldolase B 41 , and GA promotes the formation of GA-AGEs. Moreover, previous studies reported that aldolase B was not expressed in the rat brain 42 , whereas fructose-1-phosphate cleavage (aldolase) activity has been detected in the human brain 43 .…”

The Effect of Glyceraldehyde-Derived Advanced Glycation End Products on β-Tubulin-Inhibited Neurite Outgrowth in SH-SY5Y Human Neuroblastoma Cells

“…Fructose is phosphorylated to fructose-1-phosphate and then catabolized to dihydroxyacetone phosphate and GA by aldolase B [ 33 ], and then GA promotes the formation of TAGE. Moreover, it has been reported that aldolase B is not expressed in the rat brain [ 34 ], and fructose-1-phosphate cleavage (aldolase) activity has been detected in the human brain [ 35 ]. However, it is thought that the progression of AD will take over 10 years because the enzyme expression level is considered to be very low.…”