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Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction

Nature Metabolism volume 7, pages 1375–1391 (2025)Cite this article

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Abstract

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau inclusions (FTLD-tau), for which there are currently no successful treatments. Here, we show impaired glycogen metabolism in the brain of a tauopathy Drosophila melanogaster model and people with AD, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC)-derived neurons from people with FTLD-tau. Glycogen breakdown redirects glucose flux to the pentose phosphate pathway and alleviates oxidative stress. Our findings uncover a critical role for the neuroprotective effects of dietary restriction (DR) by increasing glycogen breakdown. Mechanistically, we show a potential interaction between tau protein and glycogen, suggesting a vicious cycle in which tau binding promotes glycogen accumulation in neurons, which in turn exacerbates tau accumulation which further disrupts cellular homeostasis. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy and other neurodegenerative diseases.

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Fig. 1: DR protects against neurodegeneration and extends lifespan in tau flies.
Fig. 2: Glycogen metabolism is altered in tauopathy, and glycogen breakdown prevents tauopathy-induced neurodegeneration in D. melanogaster.
Fig. 3: Glycogen breakdown in neurons shunts glucose to the PPP and reduces oxidative stress.
Fig. 4: DR activates GlyP to protect against tauopathy in D. melanogaster.
Fig. 5: Glycogen metabolism is altered in human iPSC-derived neurons from people with tauopathy.

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Data availability

Raw data for complete MS data sets for proteomic analysis have been uploaded to the MassIVE repository of the Center for Computational Mass Spectrometry at UCSD and can be downloaded using the following link: https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?task=93387e0de9b7465ab0466d3bd4bb901f

The data are also available at ProteomeXchange with the ID PXD044485. Raw data from RNA sequencing and list of targeted metabolites and their values are available in Figshare using the following link https://figshare.com/s/ad5c367a220c6cca66f8. Source data are provided with this paper.

Code availability

The code for Cox proportional hazard ratio calculation is available in Figshare using the following link: https://figshare.com/s/ad5c367a220c6cca66f8 (ref. 90).

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Acknowledgements

We would like to thank the members of the Kapahi, Ellerby, Schilling and Tracy labs for their comments throughout the paper and experiments. S.B. is supported by Larry L. Hillblom Foundation fellowship 2019-A-026-FEL. K. A. W. was supported by NIH grant T32AG000266-23 and the CatalystX award from Alex and Bob Griswold. T.A.U.H. was supported by NIH and NIA award F31AG062112, NIH/NIA training grant T32AG000266-24. This work was supported by the NIH and American Federation of Aging Research grants, NIH grants R01AG038688, R21AG054121, AG045835 and RO1-R01AG071995 and the Larry L. Hillblom Foundation to P.K. T.E.T. is supported by NIH grant R01AG070193, L.M.E. is supported by R01AG061879 and P01AG066591. We acknowledge the support of instrumentation for the TripleTOF 6600 from the NIH shared instrumentation grant 1S10 OD016281 (Buck Institute) and a Hevolution Foundation grant to the Buck Institute for Research on Aging (HF-PART-23-1422047). We thank the lab of S. Pletcher, University of Michigan Medical School, for sharing 3XEGS. We thank the Northwest Metabolomics Research Center, University of Washington, for the metabolomics analysis. We thank C. Karch for providing iPSC and isogenic control lines. Support to generate the iPSC was provided by Knight Alzheimer Disease Research Center at Washington University (NIH P30 AG066444, P01 AG03991, and P01 AG026276), NIH AG046374 (C.M.K.), and the Rainwater Charitable Organization. Schematic diagrams were generated with BioRender.com (https://biorender.com/582r1x5, https://biorender.com/xn3s24o, https://biorender.com/f73h247). We thank M. B. Feany and Scott D. Pletcher for fly strains. S.B. personally acknowledges G. T. Meyerhof, M. Dhara, P. Singh, V. Tanwar, L. Gann, W. Gutierrez, M. Gupta, V. P. Narayan, K. R. Kaneshiro, M. M. Shanmugam, G. Chawla, D. Sellegounder, K. Patel, L. Enriquez, E. Morazan, I. Emma and A. K. Cayton for their support.

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Authors and Affiliations

  1. Buck Institute for Research on Aging, Novato, CA, USA

    Sudipta Bar, Kenneth A. Wilson, Tyler A. U. Hilsabeck, Sydney Alderfer, Jordan B. Burton, Samah Shah, Anja Holtz, Enrique M. Carrera, Jennifer N. Beck, Jackson H. Chen, Grant Kauwe, Tara E. Tracy, Birgit Schilling, Lisa M. Ellerby & Pankaj Kapahi

  2. Emory Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA

    Eric B. Dammer, Fatemeh Seifar & Nicholas T. Seyfried

  3. Emory University, School of Medicine Core Labs, Atlanta, GA, USA

    Eric B. Dammer

  4. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

    Fatemeh Seifar, Ananth Shantaraman & Nicholas T. Seyfried

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  1. Sudipta Bar
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Contributions

Conceptualization: S.B. and P.K. Methodology: S.B., E.B.D., B.S., N.T.S., T.E.T., L.M.E. and P.K. Investigation: S.B., K.A.W., T.A.U.H., S.A., E.B.D., J.B.B., S.S., A.H., E.M.C., J.N.B., J.H.C., G.K., F.S. and A.S. Visualization: S.B., S.A. and E.B.D. Funding acquisition: S.B., K.A.W., T.A.U.H., B.S., T.E.T., L.M.E. and P.K. Project administration: P.K. Supervision: P.K. Writing—original draft: S.B. and P.K. Writing—review and editing: S.B., K.A.W., T.A.U.H., S.A., B.S., E.B.D., J.B.B., G.K., T.E.T., L.M.E. and P.K.

Corresponding author

Correspondence to Pankaj Kapahi.

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Competing interests

P.K. is a founder and a member of the scientific advisory board at Juvify Bio. The other authors have no competing interests.

Peer review

Peer review information

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Extended data

Extended Data Fig. 1 Impact of dietary restriction on lifespan and ROS production in tauopathy flies.

a, Lifespan of control flies (W1118 crossed with tauR406W) shows DR-mediated extension (p = 2.8164e-99) (204 and 192 flies were studied for AL and DR diets respectively). b, Lifespan of control flies (W1118 crossed with tauWT) shows DR-mediated extension (p = 9.80751e-51). For lifespan 203 and 151 flies were studied for AL and DR diets respectively. c, Mean lifespan of controls, tauR406W, and tauWT of 3 independent experiments show lifespan extension by DR. TauWT and tauR406W flies have the shortest lifespan (**p < 0.0001) than controls (n > 100 for each group). d, Lifespan of tauR406W flies shorter on both AL (p = 6.48275e-38) and DR (p = 6.03135e-57) diets than control flies (elav-Gal4 crossed with mito-GFP). For lifespan 156, 171 172 and 169 flies were studied for tauR406W AL, tauR406W DR, mito-GFP AL and mito-GFP DR were studied respectively. e, Lifespan of tauS11A is shorter (p = 1.64475e-19) than control flies (elav-Gal4 crossed with W1118) and shows DR-mediated extension (p = 3.40185e-24). For lifespan 138, 136, 96 and 85 flies were studied for control AL, control DR, tauS11A AL and tauS11A DR respectively. f, bar plot represents lethality during developmental phase in tauR406W flies and control elav-gal4 crossed with W1118. Each dot represents separate vials of embryo generated from 2:1 female: male cross. g, Lifespan of tauR406W driven by 3X Elav-Gene switch induced by RU486 is reduced (p = 9.09456e-09) than control and shows DR mediated extension (p = 4.02488e-28). For lifespan 188, 166, 185 and 168 flies were studied for the group of AL RU-, AL RU + , DR RU- and DR RU+ respectively. ‘RU-‘ and ‘RU + ‘represent vehicles control or RU486 added in food to drive the construct. h, Images of the whole-mount brain with DCFDA staining of control and tauR406W on AL and DR. i, Quantification shows increased (p < 0.0001) ROS stained by DCFDA in tauR406W flies’ brain which is rescued (p < 0.002) by DR. For ROS staining 11, 10, 14 and 12 fly brains were studied for AL RU-, AL RU + DR RU- and DR RU+ groups respectively. An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks p < 0.05 for *, p < 0.01 for **, p < 0.001 for *** and p < 0.0001 for **** by log-rank test (a, b, d, e and g) or by oneway ANOVA with Tukey’s multiple comparison test (c and i) or by two-tailed Student’s t-test (f). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 2 Impact of dietary restriction on lifespan and neurodegeneration in tauopathy flies.

a, Western blot using anti tau antibody in both control and tauR406W flies in AL and DR diets (n = 3 biological replicates each with 25 fly head). b, Densiometric analysis of western blot (n = 3 biological replicates each with 25 fly head). c, Table shows the result of Cox Proportional hazard ratio test. The coefficient (coef) is that term’s beta value, with values > 0 meaning that term increases the hazard (risk of death), and values of <0 decreasing the hazard (risk of death). The term exp(coef) is that term’s hazard ratio (HR), with the following breakdown: HR = 1: No effect, HR < 1: Reduction in the hazard, HR > 1: Increase in Hazard. The term se(coef) is the standard error for that term. The z term gives the Wald statistic value. It corresponds to the ratio of each regression coefficient to its standard error (z = coef/se(coef)). The Wald statistics evaluate whether the coefficient is statistically different from 0. The final term, Pr(>|z | ), is that row’s p-value. The rest of the table gives the confidence intervals for each variable. d, Apoptotic cell death detected by TUNEL staining in tauR406W fly whole brain shows increased TUNEL staining in tauR406W (at least 33 fly brain were studied per group). An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks p < 0.05 for *, p < 0.01 for **, p < 0.001 for *** and p < 0.0001 for **** by oneway ANOVA with Tukey’s multiple comparison test (b). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 3 Diet dependent changes in glycogen metabolism in flies overexpressing wildtype tau.

a, Venn diagram of the number of proteins upregulated in tauwt (red circle) as well as in control on AL diets (blue circle) (p < 0.0001). Dots represent enriched pathways of overlapping proteins, including fatty acid and glycogen metabolism. b, Venn diagram shows numbers of proteins downregulated in tauwt (red circle) and control on AL diets (blue circle) (p < 0.0001). Dots represent enriched pathways of overlapping proteins, including oxidative phosphorylation and glutathione metabolism. c, Venn diagram shows common upregulated protein between tauwt(red) and tauR406W(blue) (p = 0.001). d, Venn diagram shows common downregulated protein between tauwt(red) and tauR406W(blue) (p < 0.0001). e, Relative mRNA expression of GlyP in tauR406W flies and controls under AL and DR diets shows upregulation of GlyP in tauR406W on DR diets compared to control AL (p = 0.0262) and control DR (p = 0.0199) (n = 6 groups, each with 25 fly heads). f, Relative mRNA expression of AGBE in tauR406W flies and controls under AL and DR diets shows upregulation of AGBE in tauR406W on DR diets compared to control DR (p < 0.0001) or tauR406W AL (p = 0.0001) (n = 6 groups, each with 25 fly heads). g, Relative mRNA expression of GlyS in tauR406W flies and controls under AL and DR diets shows upregulation (*p = 0.111 and **p = 0.0011) of GlyS in tauR406W on DR diet (n = 6 groups each with 25 fly heads). h, Relative mRNA expression of pgm in tauR406W flies and control under AL and DR diets shows upregulation (p < 0.0001) of pgm in tauR406W on AL diet (n = 6 groups each with 25 fly head). i, Relative mRNA expression of AGBE, GlyP and pgm in RNAi flies and GlyP overexpressing flies (***p < 0.0001, **p = 0.0029, ***p < 0.0001 and **p = 0.0066 respectively). The experiments were performed using 3-4 groups each with 25 fly heads. j, Western blot shows tau expression in GlyPS15A; tauR406W, and GlyPWT (n = 25 fly heads for each tissue lysate). k, Densitometric analysis of tau expression is not changed between GlyPS15A; tauR406W and GlyPWT; tauR406W. l, GlyP enzyme activity between GlyPS15A; tauR406W (kinase dead mutant control) control and GlyPWT; tauR406W shows significant (p = 0.0002) increased activity in GlyPWT (data were collected using 320 fly heads in 4 biological replicates and two technical replicates for each group). m, Lifespan of GlyPWT; tauR406W (n = 93 flies) and GlyPS15A; tauR406W (n = 95 flies) shows no significant difference. n, Quantification of glycogen shows significant (p = 0.0058) accumulation of glycogen in the head of elav-Gal4; tauWT in compared to the control elav-Gal4xW1118 (n = 4 groups, 25 fly head in each). o, Western blot shows expression of autophagic marker Atg8(LC3) and Ref(2)P/(p62) in GlyPS15A; tauR406W, and GlyPWT (n = 25 fly heads for each tissue lysate). Samples were derive from the same experiment and that blots were processed in parallel. p, Densiometric analysis of ATG8 expression in GlyPS15A; tauR406W, and GlyPWT (n = 3) shows reduced (p = 0.0108) expression of ATG8. q, Densiometric analysis of Ref(2)P expression in GlyPS15A; tauR406W, and GlyPWT (n = 3). An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks p < 0.05 for *, p < 0.01 for **, p < 0.001 for *** and p < 0.0001 for **** by Fisher’s exact (a-d) by one-way ANOVA with Tukey’s multiple comparison test(e-h) by two tailed Student’s t-test (i, k, l, n, p and q). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 4 Metabolomic and transcriptomic changes upon over expression of GlyP in tauopathy fly heads.

a, Pathway analysis of metabolites shows amino acids metabolism, urea cycle, and PPP are the few most common pathways. in GlyPWT; tauR406W compared to GlyPS15A; tauR406W (3 replicates, each with 30 fly heads, were used). b, Quantification of reduced and oxidized glutathione ratio shows significantly (p = 0.0383) increased reduced glutathione in GlyPWT; tauR406W than GlyPS15A; tauR406W (175 flies head for 7 biological replicates were used). c, Volcano plot shows 546 transcripts (red) are upregulated and 473 transcripts (green) are downregulated (3 replicates each with 30 fly heads were used to isolate RNA). d, Pathway analysis of altered RNA shows oxidative phosphorylation, glycolysis or gluconeogenesis, ECM- receptor interaction and TCA cycle are the most common. e, TUNEL staining of GlyPWT; tauR406W with 6-AN treatment shows GlyPWT mediated reversal of apoptotic death of brains abrogate by 6-AN treatment (at least 21 fly brain were analyzed per group). An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks* for p < 0.05 by two-tailed Student’s t-test (b). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 5 Neuroprotective effects of 8-Br cAMP in tauopathy flies.

a, Western blot of PKA-C1 and actin of brain tissue lysate of control and tauR406W on AL and DR (n = 3 each tissue lysate with 25 fly heads, experiment was repeated three times independently and observed similar results). b, Normalized densitometric analysis of western blot shows decreased (p = 0.0022) abundance of PKA-C1 of tauR406W on AL. c, Survival curve shows lifespan extension (p = 3.73621e-07) of tauR406W on AL diet with 8-Br-cAMP treatment. For lifespan assay 92 to 97 flies were studied. d, Lifespan of tauR406W on DR diet with 8-Br-cAMP shows no further DR-mediated extension. For lifespan assay 92 to 97 flies were studied. e, TUNEL staining shows cAMP treatment rescues apoptotic cells in tauR406W fly brain (at least 25 fly brain were stained for TUNEL). f, Images of the whole-mount brain with DCFDA staining of control and tauR406W on AL and DR. g, Quantification shows increased (p < 0.0001) ROS stained by DCFDA in tauR406W flies’ brain which is rescued (p < 0.0001) by DR. For ROS staining 23, 24, 25 and 25 fly brains were used for control AL, control DR, tauR406W AL and tauR406W DR. h, GlyP activity in GlyP mutant flies shows reduction compared to wild type (data were collected using 320 fly heads in 4 biological replicates). An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks p < 0.05 for *, p < 0.01 for **, p < 0.001 for *** and p < 0.0001 for **** by log-rank test (c, d) or by oneway ANOVA with Tukey’s multiple comparison test (b, g), or by two-tailed Student’s t-test (h). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 6 Changes in glycogen metabolism in AD patient brains and iPSC-derived tauopathy neurons.

a, Plot showing correlation between protein abundance of tau (MTBR) and PYGB (n = 980). b, Plot showing correlation between protein abundance of tau (MTBR) and PGM (n = 980) c, Images show glycogen staining in iPSC-derived tauR406W and isogenic control (Iso-tauR406R) neurons by 2-NBDG transduced with GlyP lentivirus. d, Quantification shows glycogen staining increase (p < 0.0001) in control virus-infected tauR406W than isogenic control infected with control lentivirus, and the glycogen staining is reduced (p < 0.0001) in tauR406W cells with PYGB overexpression. e, TOM20 staining of iPSC-generated neurons shows reduced (p < 0.0001) mitochondrial density in tauR406W than isogenic control cells. f, Quantification of TOM20 staining shows reduced (p < 0.0001) mitochondrial density in tauR406W than isogenic control cells. g, TOM20 staining in PYGB overexpressing tauR406W cells show reduced mitochondrial staining in control lentivirus transduction while mitochondrial density is rescued by PYGB containing lentivirus. h, Glycogen staining with 2-NBDG in iPSC-generated tauV337M neurons and its isogenic control. i, Quantification shows increased (p < 0.0001) glycogen staining in tauV337M cells. j, Quantification of glycogen in cell lysate of tauV337M shows significantly increased (p = 0.0008) quantity than isogenic control. k, Quantification of mean fluorescence intensity of glycogenin significantly increases (p = 0.0018) in tauV337M compared to isogenic control. l, Glycogen staining in tauV337M cells and its isogenic control. m, Quantification shows significant increase (p = 0.0007) of glycogen staining in tauV337M neurons while PYGB overexpression reduces (p < 0.0001) glycogen staining in tauV337M cells compared to tauV337M treated with control lentivirus. Each dot represents an image field from n = 3 coverslips per condition for d, f, i, k and m. An asterisk (*) indicates a significant difference between experimental groups and controls, with the level of significance denoted by the number of asterisks p < 0.05 for *, p < 0.01 for **, p < 0.001 for *** and p < 0.0001 for **** by two tailed Student’s t-Test (f, i, j and k) or by two way ANOVA (d and m). Data in bar graphs are presented as mean ± s.e.m.

Source data

Extended Data Fig. 7 Tau and glycogen interaction in iPSC-derived tauopathy neurons.

a, c, Co-localization study between tau and glycogenin 1 and across the line intensity plot for tauwt neurons. b, d, Co-localization study between tau and glycogenin 1 and across the line intensity plot for tauR406W neurons. e, Western blot of elute sediment from glycogen co-sedimentation assay with either tauWT or tauP301S using anti tau antibody showed tau sedimented with glycogen f, Western blot of elute sediment from glycogen co-sedimentation assay with BSA showed BSA did not sediment with glycogen. Co-sedimentation assay was repeated 3 times with similar results.

Source data

Extended Data Table 1 Enriched pathways in the altered proteome of tauopathy fly heads
Full size table

Supplementary information

Supplementary Information

Supplementary Tables 1–4.

Reporting Summary

Supplementary Data 1

Proteomic analysis of tauR406W and tauWT on both AL and DR diets, along with a list of significantly altered proteins and GO term analysis.

Supplementary Data 2

Metabolomic analysis of GlyPS15A;tauR406W vs GlyPWT; tauR406W fly heads.

Supplementary Data 3

Transcriptomics analysis of GlyPS15A;tauR406W vs GlyPWT; tauR406W fly heads.

Supplementary Data 4

Human orthologue of common proteins altered in tau fly and people with AD.

Source data

Source Data Fig. 1

Statistical source data for Fig. 1.

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Statistical source data for Fig. 3.

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Statistical source data for Fig. 4.

Source Data Fig. 5

Statistical source data for Fig. 5.

Source Data Extended Data Fig. 1/Table 1

Statistical source data for Extended Fig. 1.

Source Data Extended Data Fig. 2/Table 2

Statistical source data for Extended Fig. 2.

Source Data Extended Data Fig. 3/Table 3

Statistical source data for Extended Fig. 3.

Source Data Extended Data Fig. 4/Table 4

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Source Data Extended Data Fig. 5/Table 5

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Statistical source data for Extended Fig. 6.

Source Data Extended Data Fig. 7/Table 7

Statistical source data for Extended Fig. 7.

Source Data Extended Data Figs. 2, 3, 5 and 7

Uncropped western blots of all western blot figure.

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Bar, S., Wilson, K.A., Hilsabeck, T.A.U. et al. Neuronal glycogen breakdown mitigates tauopathy via pentose-phosphate-pathway-mediated oxidative stress reduction. Nat Metab 7, 1375–1391 (2025). https://doi.org/10.1038/s42255-025-01314-w

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