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

Overview

1. Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
3. Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Center for Cell Lineage Atlas, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530 China
4. Department of Neurology & Institute of Neurology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200125 China
5. Lab for Future Health, Shanghai Frotiers Science Center of TCM Chemical Biology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210 China

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40035-026-00567-z.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• figshare:33118145, at figshare; found in DataCite
• figshare:33118148, at figshare; found in DataCite
• figshare:33118151, at figshare; found in DataCite

Data availability

Proteomic raw data are deposited in the iProX (https://www.iprox.cn) with Project ID IPX0012529000. Other data supporting the findings of this study are included in this article and Additional files or are available from the corresponding author on reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 7 keywords, 13 MeSH terms, 2 funders, 70 references.

Cite

This paper

Hu, X., Yu, Y., Luo, H., Li, J., Zhang, X., Wang, G., Li, J., Li, J., Chen, H., & Qiu, Y. (2026). Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease. Translational neurodegeneration, 15(1), 35. https://doi.org/10.1186/s40035-026-00567-z

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