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Background <p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.</p> Methods <p>Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.</p> Results <p>Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.</p> Conclusion <p>These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.</p>

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Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Xiaoyu Hu,
  • Ying Yu,
  • Haorui Luo,
  • Jiabing Li,
  • Xiaofei Zhang,
  • Gang Wang,
  • Jianping Li,
  • Juan Li,
  • Hongzhuan Chen,
  • Yu Qiu

摘要

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.

Methods

Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.

Results

Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.

Conclusion

These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.