Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?
Although biological effects of fructose metabolism and its byproduct, intracellular uric acid, appear critical for the survival of many animals in nature, including our ancestors, in modern society, it appears to be overengaged, increasing the risk for metabolic syndrome, obesity, diabetes, and other conditions
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uric acid translocatess NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, leading to oxidative stress that blocks the citric acid cycle (via inhibition of aconitase) and fatty acid β-oxidation. As mitochondrial function slows, glycolysis takes over, while uric acid inhibits AMP-activated protein kinase, reducing the ability to recover ATP. The effect is a reduction in ATP in the cell, activating a survival switch that includes hunger, thirst, foraging, fat accumulation, and insulin resistance.
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Uric acid translocates NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) to the mitochondria, where it causes oxidative stress, reducing fatty acid oxidation (blocking enoyl CoA hydratase) while inhibiting aconitase in the citric acid cycle
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In nature, dietary fructose from excessive intake of fruit provides a major pathway to activate this survival response, much like what occurs in the autumn when bears prepare for hibernation. However, fructose is also produced in the body via the polyol pathway, in which glucose is converted to fructose. The rate-limiting enzyme in the polyol pathway is aldose reductase, and its activity is stimulated during times of stress, such as when nutrient delivery is impaired (hypoxia or ischemia), when water supplies are low (dehydration, hyperglycemia, and hyperosmolarity), or when uric acid levels are high (reflecting degradation of nucleotides and ATP, suggestive of an energy crisis)
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However, the studies that evaluated the differences between fructose and glucose in cerebral metabolism using BOLD MRI were performed early (∼15 min), thus making it more likely to reflect true differences between fructose and glucose. The striking finding from these studies was that fructose reduced blood flow to the posterior cingulate cortex, the hippocampus, the thalamus, and the occipital cortex; however, blood flow increased to the area of the visual cortex associated with food reward. Cortical blood flow also decreased. Fructose administration also stimulated hunger and desire for food. These responses are consistent with a stimulation of the foraging response. In contrast, glucose inhibited blood flow to the hypothalamus, thalamus, insula, anterior cingulate, and striatum while stimulating blood flow to the cortex. These responses are expected to inhibit not only the foraging response but also responses involving appetite and reward.
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The brain can generate and metabolize fructose
Our hypothesis suggests that local fructose generation and metabolism may be the critical factor for how fructose induces AD because under normal circumstances, only 1%–2% of ingested fructose reaches the brain. Indeed, the brain is capable of producing fructose. As mentioned earlier, simply raising blood glucose levels increases brain fructose levels in healthy humans. Raising serum osmolality in mice by dehydration or salty food also stimulates fructose production in the brain (hypothalamus). Dietary fructose may also increase fructose production in the brain, possibly by raising uric acid levels in the brain. For example, acutely raising serum uric acid increases uric acid in both the hypothalamus and the hippocampus in association with local inflammation. In turn, uric acid stimulates fructose production and metabolism.
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Fructose is elevated in the brain of patients with AD
Sorbitol and fructose levels (both components of the polyol pathway) were significantly elevated, averaging 3–5-fold higher in all regions of the brain studied, including the hippocampus, entorhinal cortex, middle temporal gyrus, cingulate cortex, sensory and motor cortex, and cerebellum.
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Numerous studies have reported that subjects with AD have low serum uric acid levels, suggesting that this might be important to the pathogenesis. However, although serum uric acid may reflect fructose metabolism, it also is a general marker of nutrition status. Clinical manifestations of AD are often preceded by significant weight loss. Which may account for the lower serum uric acid levels on presentation of AD. This may also explain why obesity predicts AD in midlife but actually protects from AD late in life
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https://www.sciencedirect.com/science/article/pii/S0002916523000047