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Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease
Xiaoyu Hu1, Ying Yu1, Haorui Luo2
1Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Translational Neurodegeneration
|July 29, 2026
Summary
Reduced transaldolase 1 (TALDO1) impairs glucose metabolism and antioxidant defense in Alzheimer's disease (AD). Restoring TALDO1 in AD models improved neuronal function and cognition.
Area of Science:
- Neuroscience
- Metabolic pathways
- Neurodegenerative disease research
Background:
- Alzheimer's disease (AD) involves cognitive decline and synaptic dysfunction.
- Impaired glucose utilization, particularly reduced pentose phosphate pathway (PPP) flux, is implicated in AD pathogenesis.
- The precise mechanisms underlying PPP dysfunction in AD remain unclear.
Purpose of the Study:
- To investigate the mechanisms affecting PPP in Alzheimer's disease.
- To determine the contribution of PPP dysfunction to AD pathogenesis.
Main Methods:
- Proteomic analysis of synaptosomes from AD patients and controls.
- Functional studies using primary neurons and 5x FAD mouse models.
- Metabolomic, biochemical, molecular, electrophysiological, and behavioral assessments.
Main Results:
- Synaptic proteomic analysis revealed dysregulated glucose metabolism in AD.
- Transaldolase 1 (TALDO1), a key PPP enzyme, was downregulated in early AD.
- TALDO1 downregulation inhibited PPP, TCA cycle, and oxidative phosphorylation, leading to metabolic collapse, reduced antioxidant capacity, and mitochondrial dysfunction.
- Restoring TALDO1 in 5x FAD mice improved glucose metabolism, reduced oxidative stress, and rescued cognitive deficits.
Conclusions:
- TALDO1 is identified as a critical regulator of PPP impairment in Alzheimer's disease.
- TALDO1 represents a potential therapeutic target for restoring neuronal metabolic homeostasis and function in AD.
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