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Spinal cord Tau pathology induces tactile deficits and cognitive impairment in Alzheimer’s disease via dysregulation of CCK neurons

Nature Neuroscience volume 29, pages 358–373 (2026) Cite this article

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Abstract

Somatosensory processing has been shown to be correlated with brain development and cognitive function, but whether and how tactile sensory deficits affect cognition decline remains unclear. Here we show that tactile function is impaired in individuals with Alzheimer’s disease (AD), and this impairment is inversely correlated with Montreal Cognitive Assessment scores and positively correlated with Tau pathology. We observed similar deficits in presymptomatic 3×Tg AD mice and find that cholecystokinin (CCK)-expressing neurons in the spinal cord are highly vulnerable to Tau pathology. Expressing mutant Tau-P301S in spinal cord CCK-expressing neurons aberrantly activates the transcription factor c-Maf, inhibits CCK neurons and induces tactile deficits, whereas silencing Tau or c-Maf restores tactile sensation and improves cognition in AD model mice. Together, these gain- and loss-of-function studies demonstrate that Tau pathology in spinal cord CCK neurons contributes to tactile dysfunction and cognitive function. Targeting tactile sensation may be a promising strategy for predicting the progression of cognitive impairment in AD.

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Fig. 1: Tactile deficits in individuals with early-stage AD and model mice.
The alternative text for this image may have been generated using AI.
Fig. 2: Tau pathology in spinal cords of PS19 mice correlate with tactile deficits.
The alternative text for this image may have been generated using AI.
Fig. 3: Tau pathology inactivates spinal cord CCK neurons in AD.
The alternative text for this image may have been generated using AI.
Fig. 4: Silencing Tau in CCK neurons restores tactile sensation in AD.
The alternative text for this image may have been generated using AI.
Fig. 5: Chemogenetic activation of CCK neurons reverses tactile impairments in AD mice.
The alternative text for this image may have been generated using AI.
Fig. 6: The c-Maf regulon in CCK neurons mediates the tactile deficits induced by Tau pathology.
The alternative text for this image may have been generated using AI.
Fig. 7: Silencing Tau or c-Maf in CCK neurons slows the progression of AD.
The alternative text for this image may have been generated using AI.
Fig. 8: Schematic diagram of the current study.
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Data availability

The snRNA-seq data from this study have been deposited in Zenodo and are publicly accessible at https://doi.org/10.5281/zenodo.16990612 (ref. 111). cisTarget databases (Mus_musculus, mm10, refseq_r80, mc_v10_clust, gene_based database) are accessible at https://aertslab.org/. All other relevant data supporting the findings of this study are available within the manuscript, its Supplementary Information or from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

The analysis code used in this study has been deposited in Zenodo and is publicly accessible at https://doi.org/10.5281/zenodo.16990612 (ref. 111).

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Acknowledgements

We thank all the technicians and core facility in the Analytical and Testing Center, Huazhong University of Science and Technology. This study is supported by STI2030-Major Projects (2022ZD0211800) and National Natural Science Foundation of China (82325017, 82371403, 82401423, 82030032 and 82571727), the Top-Notch Young Talents Program of China of 2014 to L.-Q.Z., the Academic Frontier Youth Team of Huazhong University of Science and Technology to L.-Q.Z. and D.L., the Hubei Provincial Natural Science Foundation (2022CFA004 to L.-Q.Z., 2023AFA068 to D.L.), Changping Laboratory (2025B-07-41) and the Science and Technology Innovation Program of Hunan Province (2022RC4044 and 2024JJ7442).

Author information

Author notes

  1. These authors contributed equally: Yang Zhou, Wen-Lian Li, Zhi-Qiang Liu.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yang Zhou, Wen-Lian Li, Zhi-Qiang Liu, Wen-Qing Ai, Jia-Xin Kou, Hong-Wei Fan, You-Ming Lu & Ling-Qiang Zhu

  2. Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatric Disease, Institute of Geriatrics, Chinese PLA General Hospital and Chinese PLA Medical Academy, Beijing, China

    Zhi-Tao Han, Ya-Zhuo Hu, Hong-Hong Zhang & Jian-Jun Jia

  3. Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China

    Yan Zeng

  4. Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Zi-Yuan Guo

  5. Department of Biology, Boston University, Boston, MA, USA

    Heng-Ye Man

  6. Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Dan Liu

Authors
  1. Yang Zhou
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  2. Wen-Lian Li
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  3. Zhi-Qiang Liu
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  4. Wen-Qing Ai
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  7. Zhi-Tao Han
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  8. Ya-Zhuo Hu
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  9. Hong-Hong Zhang
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  10. Jian-Jun Jia
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  11. Yan Zeng
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  12. Zi-Yuan Guo
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  13. Heng-Ye Man
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  14. You-Ming Lu
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  15. Dan Liu
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  16. Ling-Qiang Zhu
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Contributions

L.-Q.Z. and D.L. initiated and designed the study and supervised the study. Y. Zhou, Z.-Q.L. and J.-X.K. performed the molecular biological and animal experiments. H.-W.F. performed the electrophysiology experiments. W.-L.L., Y. Zhou and W.-Q.A. performed the animal experiments. Z.-T.H., Y.-Z.H., H.-H.Z. and J.-J.J. provided the human spinal cord samples. Y. Zeng provided the clinical cohort study data. D.L., L.-Q.Z., H.-Y.M., Y.-M.L. and Z.-Y.G. provided guidance on experiments. Y. Zhou, W.-L.L., D.L. and L.-Q.Z. analyzed the data. L.-Q.Z., D.L., Y. Zhou and H.-Y.M. wrote the manuscript.

Corresponding authors

Correspondence to You-Ming Lu, Dan Liu or Ling-Qiang Zhu.

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Competing interests

L.-Q.Z., D.L., Y. Zhou and W.-L.L. are authors on patent application ‘Application of c-Maf gene and its sgRNA’, submitted to the Patent Office of the People’s Republic of China (application no. CN202410648351.7). All other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Tactile deficits in MCI and AD patients.

a, Sensory testing sites on calves (T: test regions). b, Response rates to calf stimulation at varying forces in HC, MCI, and AD groups. c, Strength of individual responses to calf stimulation. The black solid lines indicate the median values. d, Correlation between MoCA scores and tactile thresholds on the calf. e, The percentage of individuals responding to the calf stimulation with 2.0 g or 4.0 g forces in Von Frey test of HC, MCI and AD groups. f, Illustration of the VAS, which represents pain intensity: 0, no pain; 10, worst imaginable pain. g, Correlation between VAS scores and Von Frey test thresholds at 1.0 g, 2.0 g and 4.0 g stimulation. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: ordinary one- or two-way ANOVA with Dunnett’s test for multiple comparisons to HC groups (b,c,e), two-sided Pearson correlation analysis (d,g).

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Extended Data Fig. 2 Tactile deficits and intact sensations about itch, pain and motor coordination in AD mice.

a, Sticky tape test: the number of responses in 3-month-old 3×Tg and wild-type (WT) mice at different ages. b-f, The percentage of the responses in the 8–10 trials of the Von Frey test in 3×Tg and WT groups at different ages. g,h, Morris water maze: escape latency to the hidden platform during training (g) and platform crossings on day 8 (h) in 3×Tg and WT mice. i,j, Barnes maze: escape latency to the target hole during training (i) and accuracy on day 5 (j). k,l, Responses to mechanical pain stimulation (2.0 g Von Frey filaments) at the plantar surface of the paw (k) and clip applied to the base of the tail (l). m,n, Total scratching responses within 30 minutes after intradermal injection of histamine (His, m) or chloroquine (CQ, n). o,p, Paw withdrawal latencies to heat stimulation (Hargreaves, o) and responsiveness score to cooling stimulation (Ev. Cooling, p). q,r, Painful behaviors induced by capsaicin injection (q) and formalin injection into the footpad (r). s, Average number of slips during the grid test. t, Latency to stay on the rotarod at different speeds. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-way ANOVA with Bonferroni analysis (a-g,i,t), two-sided unpaired t test (h,j-s).

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Extended Data Fig. 3 Tau but not Aβ pathology occurs in the spinal cord of AD patients and model mice.

a,b, Representative immunoblots and quantification of pTau at indicated sites in the posterior horn (P) and anterior horn (A) of the lumbar spinal cord in 3×Tg and age-matched WT mice. c,d, Immunostaining of pTau at pS214, pS396, pS404, and total Tau (Tau5) in P (c) and A (d) of 3×Tg and age-matched WT mice. e, Forest plots of the association between spinal cord pTau and AD stages analyzed by a fixed-effects model. M-H, Mantel-Haenszel. Data are presented as Odds Ratio (OR) [95% Cl]. Statistical tests: Mantel-Haenszel method. f, AT8 immunostaining in entorhinal cortex (Ent), primary somatosensory cortex (S1), hippocampal CA1 region (CA1), cuneate nucleus (Cu), corticospinal tract (CST), and dorsal root ganglion (DRG) of 3-month-old WT and PS19 mice. g, Representative H&E staining of skin from 3-month-old WT and PS19 mice. h, Representative immunofluorescence images of the lumbar dorsal spinal cord from PS19 mice stained with antibodies against pT231 with NeuN, GFAP or Iba1. i-k, Correlation of weighted average \(\overline{{pTau}}\) levels with behavioral performance in 3×Tg and WT mice: sticky tape test (i), von Frey test (j), and dynamic touch test (k). l-o, ELISA of secreted Aβ42 and Aβ40 in the posterior horn and anterior horn of the spinal cord in 3×Tg (l,m), PS19 (n,o) and age-matched WT mice. p, Immunostaining of Aβ at antibody 6E10 in the lumbar posterior horn of WT and 3×Tg mice. q, Representative dot blot (top) and quantification (bottom) of oligomeric Aβ (A11) in lumbar spinal cords of WT and 3×Tg mice. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-way ANOVA with Bonferroni analysis (b,l-o), two-sided Pearson correlation analysis (i-k), two-sided unpaired t test (q). Data are representative of independent experiments: three (a); two (c,d,f–h,p,q).

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Extended Data Fig. 4 Tau mutant mice exhibit aberrant innocuous touch but not itch or pain sensitivity.

a-l, Responses of age-matched WT and PS19 (a-d), P301L (e-h), APP/PS1 (i-l) mice in tactile sensation tests: number of responses in the sticky tape test (a,e,i); percentage of responses in Von Frey test (b,f,j); percentage of paw withdrawal responses in the dynamic touch test (c,g,k); and proportion of abnormalities in tactile sensation validated by sticky tape, Von Frey, and dynamic touch tests (d,h,l). m, Immunostaining of pTau at pT231 in the posterior horn of spinal cord in WT, APP/PS1, and P301L mice. n,o, Responses to mechanical pain stimulation (2.0 g Von Frey filaments) in WT, PS19, P301L, and APP/PS1 mice: at the plantar surface of the feet (n) and with a clip applied to the base of the tail (o). p,q, Total scratching responses within 30 minutes after intradermal injection of His (p) or CQ (q) in WT, PS19, P301L, and APP/PS1 mice. r,s, Paw withdrawal latencies to heat stimulation (Hargreaves, r) and responsiveness score to cooling stimulation (Ev. Cooling, s). t,u, Painful behaviors induced by capsaicin injection (t) and formalin injection into the footpad (u). v, Average number of slips during the grid test. w, Latencies to stay on the rotarod at different speeds. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (a,c,e,g,i,k), two-way ANOVA with Bonferroni analysis (b,f,j), ordinary one- or two-way ANOVA with Dunnett’s multiple-comparisons test (n-w). Data are representative of two independent experiments (m).

Source data

Extended Data Fig. 5 Expression of pTau or c-fos in spinal cord interneurons of PS19 mice and AD patients.

a-d, Representative immunofluorescence images and quantification of pTau in different excitatory or inhibitory interneurons of spinal cord from PS19 mice by staining with antibodies against pT231 (a,b) or pS262 (c,d), and FISH for Cerebellin-2 (Cbln2), Insulin-like growth factor binding protein 5 (Igfbp5), Serotonin receptor 6 (5HTr6), Neurogenic differentiation factor-4 (NeuroD4), PKCγ, RAR-related orphan receptor beta (Rorβ), Kv channel interacting protein-2 (Kcnip2), Cadherin-3 (Cdh3), and CCK, with DAPI counterstain. e, Representative immunofluorescence images of pTau in different excitatory or inhibitory interneurons of spinal cord from AD patient by staining with antibodies against AT8 and antibodies against Cbln2, Igfbp5, 5HTr6, NeuroD4, PKCγ, Rorβ, Kcnip2, Cdh3, and CCK, with DAPI counterstain. f,g, Representative immunofluorescence images of dorsal spinal cord from PS19 mice by staining with antibodies against CCK or PKCγ (laminae IIiv marker) and c-fos, with DAPI counterstain. h, Representative immunofluorescence images and quantification of CCK neurons in posterior horn cells from 2- and 7-month-old PS19 mice. i, Representative immunofluorescence images and quantification of CCK neurons in posterior horn cells in ONDs and AD patients. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (h). Data are representative of two independent experiments (a,c,f,g,h), Data are shown as individual points with mean, and no statistical comparison was performed when n < 3 (i).

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Extended Data Fig. 6 Overexpression of Tau in spinal CCK neurons impairs tactile function and neuronal excitability but not nociceptive behaviors.

a, Schematic showing injection of rAAV2/9-hSyn-DIO-MAPT (P301S)-EGFP (Tau) and control virus (EGFP) into the posterior horn of CCK-cre mice. Middle right, ISH images for cck mRNA probe (from Allen Brain Atlas); lower right, GFP fluorescence distribution. b, Representative images showing EGFP expression in CCK neurons. c, Representative images showing pTau at pT231 in EGFP-positive neurons. d-f, Behavioral responses in Cre mice with or without Tau injection: The number of responses in the sticky tape test (d), the percentage of paw withdrawal responses in the dynamic touch test (e), the percentage of responses in Von Frey test (f). g, Representative traces of sEPSC recorded from CCK neurons of laminae IIi-IV of spinal cord in mice treated as in panel a. h,i, Quantification of sEPSC frequency (h) and amplitude (i) in panel g. j, Representative action potentials from CCK neurons of laminae IIi-IV of spinal cord in response to depolarizing current step. k, Left, A plot showing firing rates versus depolarizing currents; right, differences in the firing rates in panel j. l,m, Responses to mechanical pain stimulation in Cre mice with or without Tau injection: at the plantar surface of the paw (l) and with a clip applied to the base of the tail (m). n,o, Total scratching responses within 30 minutes after intradermal injection of CQ (n) or His (o). p,q, Paw withdrawal latency to Hargreaves (p) and responsiveness score to Ev. Cooling (q). r,s, Painful behaviors induced by capsaicin injection (r) and formalin injection into the footpad (s). t, Average number of slips during the grid test. u, Latencies to stay on the rotarod at different speeds. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (d,e,h,i,l-t), two-way ANOVA with Bonferroni analysis (f,k,u). Data are representative of two independent experiments (a-c).

Source data

Extended Data Fig. 7 c-Maf regulates neuronal activity-related genes.

a,b, Representative immunofluorescence images and quantification of c-Maf and CCK in posterior horn cells of WT and PS19 mice. c, Representative immunofluorescence images and quantification of c-Maf and AT8 in posterior horn cells of WT and PS19 mice. d, Correlation between fluorescent intensities of c-Maf and AT8 in WT and PS19 mice. e, Relative mRNA levels of c-Maf target genes in N2a cells after transfection with pcDNA3.1-c-Maf (c-Maf) or vector control (Con). f, Schematic of luciferase experiment. Promoter sequences (wild type and binding site mutant (mut)) of c-Maf target genes (Nrn1, Dlg2) were inserted into pGL3-Basic vector, co-transfected with pRL-TK (Renilla luciferase reporter vector) and pcDNA3.1-c-Maf (or vector) into HEK293 cells. Cell lysates were collected 48 h later to evaluate luciferase activities at 570 nm and 480 nm. g,h, Relative luciferase activity in HEK293 cells transfected with pRL-TK and pGL3-Basic vector containing wild type or mutant Dlg2 or Nrn1 promoter sequence, with pcDNA3.1-c-Maf (or vector). i,j, The sgc-Maf-N2a (or scrambled control) cells transfected with pRL-TK and pGL3-Basic vector containing wild type or mutant Dlg2 (i) or Nrn1 (j) promoter sequence, and P301S-Tau or vector. Relative luciferase activities analyzed 48 h later. k,l, Protein levels of c-Maf, Dlg2, and Nrn1 in spinal cord of WT and PS19 mice (k) and in N2a cells infected with AAV-hTau (oe-Tau) or control virus (Vector) 48 h post-infection (l), measured by western blotting and quantified. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (b), two-sided Multiple Mann-Whitney test (e), two-sided multiple t test (g,h,k,l), two-sided Pearson correlation analysis (d), ordinary one-way ANOVA with Dunnett’s multiple-comparisons test (i,j). Data are representative of two independent experiments (a,c), three independent experiments (k,l).

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Extended Data Fig. 8 Overexpression of c-Maf in CCK neurons impairs tactile behavior and neuronal excitability but not nociceptive behaviors.

a, Schematic showing injection of rAAV-hSyn-DIO-c-Maf-EGFP (c-Maf) and control virus (EGFP) in CCK-cre mice. Middle right, ISH images for cck mRNA probe (from Allen Brain Atlas); lower right, GFP fluorescence distribution. b-d, Behavioral responses in mice treated as in panel a: The number of responses in the sticky tape test (b), the percentage of responses in Von Frey test (c), the percentage of paw withdrawal responses in the dynamic touch test (d). e-g, Representative sEPSC traces (e) and quantitative analysis of frequency (f) and amplitude (g) in CCK neurons of laminae IIi-IV dorsal horn. h, Representative action potentials from CCK neurons of laminae IIi-IV of spinal cord in response to depolarizing current step. i, Left, A plot showing firing rates versus depolarizing currents; right, differences in the firing rates. j-s, Responses in acute mechanical pain (j,k), acute chemical itch (l,m), thermal and chemical pain (n-q), and motor coordination (r,s) in CCK-cre mice with c-Maf overexpression or control virus. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (b,d,f,g,j-r), two-way ANOVA with Bonferroni analysis (c,i,s). Data are representative of two independent experiments (a).

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Extended Data Fig. 9 Construction of stable c-Maf knockdown N2a cell lines by CRISPR/dCas9 systems and knockdown c-Maf relieves tactile deficits caused by Tau overexpression in CCK neurons.

a, Diagram of experimental procedures for screening effective sgRNA targeting c-Maf using CRISPR-dCas9 systems. b,c, N2a cells cultured in 6-well plates and transfected with different sgRNA plasmids. After 48 h, medium was replaced and puromycin at different concentrations (10, 5, 2.5, 1.25, 0.62, 0 μg/mL) was added. Cell growth was observed after 7 days (b) and survival probabilities quantified (c). d, Expression levels of c-Maf in dCas9-sgc-Maf cells detected by western blotting (top) and quantified (bottom). e, Schematic showing injection of rAAV2/9-hSyn-DIO-MAPT (P301S)-mCherry (Tau) or control virus (mCh) and pLV-hU6-sgc-Maf-hUbC-DIO-dCas9-KRAB-GFP (sgc-Maf) or control virus (GFP) into CCK-cre mice. f, Representative images showing pTau at pT231 and c-Maf in mCherry-positive neurons. g-i, Behavioral responses in CCK-cre mice treated as in panel e: The number of responses in the sticky tape test (g), the percentage of paw withdrawal responses in the dynamic touch test (h), the percentage of responses in the Von Frey test (i). j-l, Representative sEPSC traces (j) and quantitative analysis of frequency (k) and amplitude (l) in CCK neurons of IIi–IV dorsal horn in mice treated as in panel e. m, Left, A plot showing firing rates versus depolarizing currents; right, differences in the firing rates in CCK neurons of IIi–IV dorsal horn in mice treated as in panel e. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: one-way ANOVA with Dunnett’s multiple-comparisons test(d), two-sided unpaired t test (g,h,k,l), two-way ANOVA with Bonferroni analysis (i,m). Data are representative of three independent experiments (b,f), two independent experiments (d).

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Extended Data Fig. 10 Behavioral changes of AD mice with silencing of Tau or c-Maf in CCK neurons.

a, In Morris Water Maze task, the accuracy of mice moving in four quadrants was recorded. The target quadrant (Quadrant II) is highlighted in light yellow. b, In Open Filed Test, total time in the central area was recorded. c, In Elevated Plus Maze, number of entries into the open arm and close arm were recorded. Panel a,b,c, related to Fig. 6a-g. d-f, Behavioral analyses as in a-c in another cohort (mCh and siTau mice), related to Fig. 6h–q. g-i, Behavioral analyses as in panel a-c in an additional cohort (GFP and sgc-Maf), related to Fig. 6 r-aa. j-l, Behavioral responses in mCh and siTau mice: The number of responses in the sticky tape test (j), the percentage of responses in the Von Frey test (k) and the percentage of paw withdrawal responses in the dynamic touch test (l). m,n, Morris water maze: escape latency to the hidden platform during training (m) and platform crossings on day 8 (n) in mCh and siTau mice. o-q, Behavioral responses like panel j-l in EGFP and Tau mice (wild type human Tau selectively overexpressed in spinal cord CCK neurons in MAPT-KO mice). r,s, Morris water maze like panel m-n in mice treated as in panel o-q. t-v, Behavioral responses like panel j-l in EGFP and c-Maf mice (c-Maf selectively overexpressed in spinal cord CCK neurons in MAPT-KO mice). w,x, Morris water maze like panel m-n in mice treated as in panel t-v. Each point represents an individual. Sample sizes (n) are indicated in parentheses or on each bar. Data are presented as mean ± s.e.m. Statistical tests: two-sided unpaired t test (b,c,e,f,h,i,j,l,n,o,q,s,t,v,x), two-way ANOVA with Bonferroni analysis (a,d,g,k,m,p,r,u,w).

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Supplementary Figs. 1–4, Supplementary Table 1–7, Supplementary Methods and Supplementary Methods-Only References.

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Sticky tape test in WT mice.

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Sticky tape test in 3×Tg mice.

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Statistical source data for Figs. 1–7 and Extended Data Figs. 1–10.

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Unprocessed western blots and dot blots for Fig. 2 and Extended Data Figs. 3, 7 and 9.

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Zhou, Y., Li, WL., Liu, ZQ. et al. Spinal cord Tau pathology induces tactile deficits and cognitive impairment in Alzheimer’s disease via dysregulation of CCK neurons. Nat Neurosci 29, 358–373 (2026). https://doi.org/10.1038/s41593-025-02137-4

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