Abstract Alzheimer’s disease (AD) is associated with the formation of tau-hyperphosphorylated neurofibrillary tangles (NFTs). Impaired glucose metabolism has been proposed as a major risk factor in AD severity, with many enzymes and pathways associated with glucose metabolism found to be compromised. The use of additional glucose has been suggested to reduce AD severity. However, the exact role of glucose metabolism in disease progression is still under investigation. In this study, we found that adding glucose to tau-expressing worms not only shortens their lifespan but also induces tau phosphorylation on critical serine and threonine residues. Increased phosphorylation of tau is associated with the formation of NFTs and increased disease severity. O-β-GlcNAcylation may inhibit phosphorylation. We hypothesized that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectations, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene, interferes with and reduces tau phosphorylation. Conversely, reducing O-β-GlcNAcylation by suppressing the O-GlcNAc transferase (ogt-1) gene increases tau phosphorylation. Our results suggest that glucose addition may induce selective O-β-GlcNAcylation on some proteins but not on tau. High levels of glucose exacerbate disease progression by promoting tau hyperphosphorylation. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in tau models of AD in C. elegans. Our observations indicate that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression. Key messages <UnorderedList Mark="Bullet"> <ItemContent> Formation of tau hyperphosphorylated neurofibrillary tangles are hallmarks of Alzheimer’s disease (AD) in aged patients. </ItemContent> <ItemContent> Glucose metabolism may affect the AD pathogenesis. </ItemContent> <ItemContent> Glucose was found to induce tau phosphorylation. </ItemContent> <ItemContent> Glucose intake was not able to induce overall O-β-GlcNAcylation. </ItemContent> <ItemContent> Collectively, higher glucose levels in diet were associated with induced disease severity. </ItemContent> </UnorderedList>

Glucose enrichment reduces lifespan and promotes tau phosphorylation in human tau-expressing C. elegans, unaffected by O-β-GlcNAcylation induction

期刊论文
发表日期：

2025年2月10日

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Waqar Ahmad,
Khadija Shabbiri

摘要

Abstract

Alzheimer’s disease (AD) is associated with the formation of tau-hyperphosphorylated neurofibrillary tangles (NFTs). Impaired glucose metabolism has been proposed as a major risk factor in AD severity, with many enzymes and pathways associated with glucose metabolism found to be compromised. The use of additional glucose has been suggested to reduce AD severity. However, the exact role of glucose metabolism in disease progression is still under investigation. In this study, we found that adding glucose to tau-expressing worms not only shortens their lifespan but also induces tau phosphorylation on critical serine and threonine residues. Increased phosphorylation of tau is associated with the formation of NFTs and increased disease severity. O-β-GlcNAcylation may inhibit phosphorylation. We hypothesized that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectations, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene, interferes with and reduces tau phosphorylation. Conversely, reducing O-β-GlcNAcylation by suppressing the O-GlcNAc transferase (ogt-1) gene increases tau phosphorylation. Our results suggest that glucose addition may induce selective O-β-GlcNAcylation on some proteins but not on tau. High levels of glucose exacerbate disease progression by promoting tau hyperphosphorylation. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in tau models of AD in C. elegans. Our observations indicate that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

Key messages

Formation of tau hyperphosphorylated neurofibrillary tangles are hallmarks of Alzheimer’s disease (AD) in aged patients.

Glucose metabolism may affect the AD pathogenesis.

Glucose was found to induce tau phosphorylation.

Glucose intake was not able to induce overall O-β-GlcNAcylation.

Collectively, higher glucose levels in diet were associated with induced disease severity.