The Role of Fructose Metabolism in Alzheimer's Disease

The question asks about the role of fructose metabolism in Alzheimer's disease (AD). Let's break this down step by step, drawing on the provided source and my knowledge.

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First, we need to understand the basics of AD. AD is a neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, tau tangles, neuroinflammation, and neurodegeneration[1]. The provided source highlights that while emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals, and alternative treatments are needed[1].

Next, we need to understand the role of microglia in AD. Microglia, the brain's resident macrophages, play a crucial role in AD neuropathogenesis by regulating Aβ phagocytosis, tau spreading, inflammation, and lipid homeostasis[1]. Targeting microglia holds potential for developing new AD treatments[1].

Now, let's connect fructose metabolism to microglia and AD. The provided source suggests that microglial fructose metabolism may be a novel therapeutic target for AD[1]. Microglia undergo metabolic shifts, including increased glycolysis and fructose metabolism, in aging and AD[1]. The fructose transporter SLC2A5 (GLUT5) is predominantly expressed by microglia in the brain, and its expression is upregulated in aging and disease[1].

The ability of microglia to transport and utilize fructose, coupled with the well-established role of fructose in metabolic dysfunction, supports the notion that microglial fructose metabolism may be a novel potential therapeutic target for AD[1].

The source highlights that fructose enters the cell via the fructose transporter GLUT5, which is predominantly expressed by microglia[1]. The first step in fructolysis is the conversion of fructose to fructose-1-phosphate (F1P) by ketohexokinase (KHK), which is also abundantly expressed by microglia[1].

The provided source also mentions that targeting fructose uptake and breakdown could prevent microglial dysfunction[1]. The distinct expression pattern of fructose-related proteins in microglia highlights fructose metabolism as a novel therapeutic target that can ameliorate the metabolic reprogramming of microglia in AD progression[1].

Therefore, the answer to the question is: Excess fructose metabolism accelerates amyloid-beta and tau pathology.

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