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GDF1 ameliorates cognitive impairment induced by hearing loss

Nature Aging volume 4, pages 568–583 (2024)Cite this article

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Abstract

Hearing loss is associated with an increased risk of Alzheimer disease (AD). However, the mechanisms of hearing loss promoting the onset of AD are poorly understood. Here we show that hearing loss aggravates cognitive impairment in both wild-type mice and mouse models of AD. Embryonic growth/differentiation factor 1 (GDF1) is downregulated in the hippocampus of deaf mice. Knockdown of GDF1 mimics the detrimental effect of hearing loss on cognition, while overexpression of GDF1 in the hippocampus attenuates the cognitive impairment induced by deafness. Strikingly, overexpression of GDF1 also attenuates cognitive impairment in APP/PS1 transgenic mice. GDF1 activates Akt, which phosphorylates asparagine endopeptidase and inhibits asparagine endopeptidase-induced synaptic degeneration and amyloid-β production. The expression of GDF1 is downregulated by the transcription factor CCAAT-enhancer binding protein-β. These findings indicate that hearing loss could promote AD pathological changes by inhibiting the GDF1 signaling pathway; thus, GDF1 may represent a therapeutic target for AD.

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Fig. 1: Hearing loss promotes AD pathologies and cognitive impairment.
Fig. 2: Expression of Gdf1 is decreased in WT and APP/PS1 mice with hearing loss.
Fig. 3: Overexpression of GDF1 in the hippocampus attenuates the cognitive dysfunction caused by deafness.
Fig. 4: GDF1 activates Akt and inhibits AEP activity.
Fig. 5: Knockdown of GDF1 aggravates AD pathology.
Fig. 6: C/EBPβ inhibits the expression of GDF1.

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Data availability

Additional data that support the findings of this study are available from the corresponding authors upon reasonable request. All the RNA-seq results presented in this paper are based on the processed data generated by bioinformatics specialists at the BGI, which are presented in Supplementary Table 1. The raw reads of the RNA-seq analyses presented in Fig. 2a–d are not available because they were deleted by BGI before they could be retrieved by the authors at the time of acceptance of this manuscript. Source data are provided with this paper.

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (no. 2019YFE0115900), the National Natural Science Foundation of China (nos. 82271447 and 81822016) and the Innovative Research Groups of Hubei Province (no. 2022CFA026).

Author information

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China

    Lina Pan, Chunrui Li, Lanxia Meng, Guoxin Zhang, Ye Tian, Dandan Su, Xingyu Zhang, Min Xiong, Tingting Xiao, Danhao Xia & Zhentao Zhang

  2. Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Li Zou

  3. Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Sen Chen & Yu Sun

  4. PET-CT/MRI Center, Molecular Imaging Center, Renmin Hospital of Wuhan University, Wuhan, China

    Zhengyuan Hong

  5. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Zhentao Zhang

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Contributions

Z.Z. conceived the project and designed the experiments. L.P. and C.L. performed most of the experiments. L.M., G.Z., D.S., X.Z., M.X. and Z.H. helped with the cell culture and animal experiments. L.Z. and D.X. performed the electrophysiological experiments. Y.T. and T.X. helped analyze the RNA-seq data. S.C. and Y.S. helped with the ABR experiments.

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Correspondence to Zhentao Zhang.

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Nature Aging thanks Hongbo Zhao, Shinichi Someya, Yadong Huang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Cochlear ablation promotes AD pathologies.

a, b, Representative images of Aβ deposition in APP/PS1 mice 6 m after cochlear ablation (n = 6 mice per group). AuC, auditory cortex; TeA, temporal association cortex. Scale bar, 200 μm. c, d, ThS staining of Aβ plaques in the hippocampus of WT and APP/PS1 mice (n = 6 mice per group). Scale bar, 50 μm. e, RT-PCR shows the mRNA levels of mAPP and HuAPP in the hippocampus (n = 6 mice per group). f, Western blot analysis of ADAM10 and BACE1 levels in the hippocampus (n = 5 mice per mouse). Right, quantification analysis. Data are presented as means ± SEM. P values were determined by two-sided Mann-Whitney test (b, d) or two-way ANOVA (e, f). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., not significant.

Source data

Extended Data Fig. 2 Cochlear ablation leads to synaptic dysfunction.

a, b, Morris water maze test showed no difference in escape latency (a) or swim speed (b) in the visible training (n = 13 in the WT-SO group, n = 7 in the WT-CA group, n = 15 in the APP/PS1-SO group, n = 11 in the APP/PS1-CA group). c-g, Electron microscopy of synapses. Shown are the representative images (c), synaptic density (d), the average thickness of PSD (e), length of the active zone (f), and width of synaptic clefts (g). Scale bar, 2 μm. (n = 6 fields per group). h, Western blot analysis of synaptic proteins in the hippocampus (n = 5 mice per group). Right, quantification of PSD95, synapsin 1, synaptophysin, and VAMP2. Data are presented as means ± SEM. P values were determined by two-way ANOVA (a, b, d-h). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., not significant.

Source data

Extended Data Fig. 3 Administration of kanamycin promotes AD pathologies.

a, Schematic diagram of the experimental procedure and timeline. Subcutaneous injection of normal saline (NS) or kanamycin (Kana) was conducted on WT and APP/PS1 mice at 3 months of age. b, ABR threshold results. The left panel shows click-evoked ABR thresholds at 1 month after saline or kanamycin injection. The right panel shows pure tone-evoked ABR thresholds 1 month and 6 months after modeling (n = 13 in the WT-NS group, n = 14 in the WT-Kana group, n = 10 in the APP/PS1-NS group, n = 8 in the APP/PS1-Kana group). c, Immunofluorescence (red) and ThS staining (green) of Aβ deposition. AuC, auditory cortex. Scale bar, 50 μm. d, Quantitative analysis of immunofluorescence (n = 8 mice per group). e, Western blot detection of APP and CTF fragments in hippocampal lysates from WT and APP/PS1 mice at 6 months after kanamycin injection (n = 5 mice per group). f, Quantification of Western blots. g, RT-PCR shows the mRNA levels of mAPP and HuAPP in the hippocampus (n = 6 mice per group). h, Western blot analysis of ADAM10 and BACE1 levels in the hippocampus (n = 5 mice per group). i, Quantification analysis of (h). Data are presented as means ± SEM. P values were determined by two-sided Mann-Whitney test (d), or two-way ANOVA (b, f, g, i). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s., not significant.

Source data

Extended Data Fig. 4 Kanamycin-induced hearing loss leads to cognitive impairment.

a-f, Spatial memory was determined in the Morris water maze test. Shown are the escape latency (a) and swim speed (b) in the visible train, escape latency in the hidden training (c-e), and time in the target zone in the probe trial (f). AUC, area under the curve. g, h, Working memory was assessed in the Y-maze test 6 months after kanamycin injection in WT and APP/PS1 mice. n = 13 in the WT-NS group, n = 14 in the WT-Kana group, n = 10 in the APP/PS1-NS group, n = 8 in the APP/PS1-Kana group. i, Western blot analysis of synaptic proteins in the hippocampus. j, Quantification of PSD95, synapsin 1, synaptophysin, and VAMP2 (n = 5 mice per group). Data are presented as means ± SEM. P values were determined by two-way ANOVA (a, b, d, e, g, j) or Kruskal-Wallis tests (f, h). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s., not significant.

Source data

Extended Data Fig. 5 KEGG pathway enrichment analysis in WT mice.

a, Top 20 KEGG pathway terms gathering most DEGs in WT mice as determined by enrichment analysis. b, KEGG interaction network illustrating the relationship among the most significant DEGs in WT mice ranked by q-values.

Extended Data Fig. 6 GDF1 levels in mouse brains injected with AAV-GDF1 or AAV-shGDF1.

a, Levels of GDF1 in hippocampal tissue from WT or APP/PS1 mice injected with AAV-GDF1 or control AAVs. b, Quantification analysis of (a). n = 5 mice per group. c, Double-labeling immunofluorescence of hippocampal sections from control, GDF1-overexpressing (GDF1 OE), and GDF1-knockdown (GDF1 KD) mice. GDF1 (red) and MAP2, Iba1, GFAP (green). Regions in the box are enlarged at right. Arrowheads indicate colocalization. Intensity trace are plotted below. The upper right panel shows the quantification of the fraction of GDF1 colocalizing with MAP2, Iba1, or GFAP. The bottom right panel shows the quantification of GDF1 fluorescence intensity in control, GDF1 OE, and GDF1 KD mice. AFU, Arbitrary fluorescence intensity. n = 5 fields per group. Scale bar, 20 μm. Data are presented as means ± SEM. P values were determined by two-way ANOVA (b) or one-way ANOVA (c). *P < 0.05, **P < 0.01.

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Extended Data Fig. 7 GDF1 knockdown inhibits AKT signaling pathway.

a, Levels of GDF1 in hippocampal tissues from WT or APP/PS1 mice injected with AAV-shGDF1 or control virus. b, Quantitative analysis of (a). n = 5 mice per group. c, Western blot analysis of AKT, p-AKT, AEP, and APP N585 in the hippocampus. d, Quantitative analysis of (c) (n = 5 mice per group). e, AEP activity assay. n = 6 mice per group. Data are presented as means ± SEM. P values were determined by two-way ANOVA (b, d, e). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., not significant.

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Extended Data Fig. 8 GDF1 overexpression attenuates AD pathogenesis.

a, Schematic diagram of the experimental procedure and timeline. b, Levels of GDF1 in hippocampal tissue of WT or APP/PS1 mice injected with GFP-GDF1 virus or control virus. c, Quantification analysis of (b) (n = 5 mice per group). d, The expression of GFP in mice injected with GFP-vector or GFP-GDF1 virus. Scale bar, 200 μm. e, Pure tone-evoked ABR thresholds 1 month and 5 months after AAV injection (n = 12 in the WT-Vector group, n = 12 in the WT-GDF1 group, n = 8 in the APP/PS1-Vector group, n = 8 in the APP/PS1-GDF1 group). f-k, Spatial memory was determined in the Morris water maze test. Shown are the escape latency (f) and swim speed (g) in the visible train, the escape latency in the hidden training (h-j), and time in the target zone in the probe trial (k). AUC, area under the curve. n = 12 in the WT-Vector group, n = 12 in the WT-GDF1 group, n = 8 in the APP/PS1-Vector group, n = 8 in the APP/PS1-GDF1 group. l, m, IHC analysis of Aβ deposition in the hippocampus and retrosplenial area (RSP) of APP/PS1 mice. Brain slices were stained with human Aβ antibody. Scale bar, 50 μm. n = 6 mice per group. n, o, Effect of GDF1 on APP processing in the hippocampus (n = 5 mice per group). Data are presented as means ± SEM. P values were determined by two-sided Kruskal-Wallis tests (k), two-sided Mann-Whitney test (m), or two-way ANOVA test (c, f, g, i, j, o). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n.s., not significant.

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Supplementary information

Reporting Summary

Supplementary Table 1

RNA-seq data.

Supplementary Table 2

Sequences of oligonucleotides.

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Pan, L., Li, C., Meng, L. et al. GDF1 ameliorates cognitive impairment induced by hearing loss. Nat Aging 4, 568–583 (2024). https://doi.org/10.1038/s43587-024-00592-5

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