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Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease

Nature Neuroscience volume 23, pages 1567–1579 (2020)Cite this article

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Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of individuals with AD. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in hilar astrocytes of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.

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Fig. 1: Accumulation of tau isoforms in the hilus of individuals with AD.
Fig. 2: 3R tau inclusions increase in the hilar astrocytes of individuals with AD.
Fig. 3: Viral strategy to specifically target hilar astrocytes.
Fig. 4: Tau isoforms differentially affect mitochondria in hilar astrocytes in vivo.
Fig. 5: Tau isoforms differentially alter mitochondrial function in astrocytes in vitro.
Fig. 6: Impact of astrocytic tau overexpression on hippocampal function.
Fig. 7: Tau 3R overexpression in hilar astrocytes induces a spatial memory deficit that is restored by NRG1p injection.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request. The map sequence for LV construction and microscopy acquisition data have been deposited in Zenodo.org at https://doi.org/10.5281/zenodo.3953694. Source data are provided with this paper.

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Acknowledgements

This study was supported by a Synapsis Foundation fellowship awarded to K.R. and the Lausanne University Hospital (CHUV) and by the Swiss National Science Foundation (31003A_173128 to N.T. and K.R.). L.B., M.C., S.H., R.C. and S.E. were supported by the Programme Investissement d’avenir LabEx (laboratory excellence), DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), France Association PSP, the LiCEND (Lille Centre of Excellence in Neurodegenerative Disorders), CNRS, Inserm, Métropole Européenne de Lille, Univ. Lille, FEDER and DN2M. The authors thank the Cellular Imaging Facility of the University of Lausanne for their technical support; F. Magara at the Center for Behavioral Studies of the Lausanne University Hospital, for assistance with the behavioral testing; and H. Imamura of Kyoto University for the MitoGoAteam2 plasmid. We warmly thank C. Rampon and M.C. Miquel at the University of Toulouse and G. Vachey, M. Humbert-Claude, L. Tenenbaum and R. Jenni at the Lausanne University Hospital for their precious help. We also thank S. Sultan, F. Cassé and T. Larrieu for their critical reading of the manuscript and helpful comments.

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  1. These authors contributed equally: Nicolas Toni, Nicole Déglon.

Authors and Affiliations

  1. Department of Psychiatry, Center for Psychiatric Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland

    Kevin Richetin, Pascal Steullet, Enea Parietti, Kim Q Do, Geneviève Leuba & Nicolas Toni

  2. Laboratory of Neurotherapies and Neuromodulation, Neuroscience Research Center (CRN), Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland

    Kevin Richetin, Mathieu Pachoud, Mathischan Maheswaran, Catherine Pythoud, Maria Rey & Nicole Déglon

  3. Department of Clinical Neuroscience (DNC), Laboratory of Neurotherapies and Neuromodulation, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland

    Kevin Richetin, Mathieu Pachoud, Mathischan Maheswaran, Catherine Pythoud, Maria Rey & Nicole Déglon

  4. Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France

    Romain Perbet, Sabiha Eddarkaoui, Séverine Bégard, Raphaëlle Caillierez, Sophie Halliez, Luc Buée & Morvane Colin

  5. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland

    Paola Bezzi

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Contributions

K.R. conceived the project and co-supervised the study, acquired and analyzed the data and wrote the manuscript. G.L. collected human samples and performed immunostainings. M.P. and R.P. acquired and analyzed microscopy data. M.M. acquired the data for LV tropism. P.B. designed the calcium imaging experiments. P.S. and K.D. designed and performed the electrophysiology experiments. M.R. cloned the plasmids and produced the LV. C.P., E.P. and R.C. produced the in vitro cultures and immunohistochemistry. S.H., S.B. and M.C. acquired and analyzed data. M.C. and L.B. helped with the research design and critically revised the manuscript. N.T. designed and supervised the study and wrote the manuscript. N.D. designed the LVs and supervised the study.

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Correspondence to Kevin Richetin or Nicolas Toni.

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Extended data

Extended Data Fig. 1 Differential Aβ accumulation in the hilus of AD patients.

a, Histogram showing the age of patients. b, Histogram showing the post-mortem delay of patients. c, Histogram showing the sex of patients. d, Photomicrographs of the human hippocampus showing the density of Aβ in healthy patient and AD donors. The different areas are indicated as black overlay. e, Histogram showing the density of Aβ in the different hippocampal regions of healthy and AD donors. f, Correlations between Aβ plaques density and Braak stage for patients, for each hippocampal area. g, Table showing the correlation values and P values. Scale bars: 250 µm (d). N = patients/sections per patient; N = 9/4 for Control, N = 6/4 for AD (P-Tau−/Aβ-), N = 6/4 for AD (P-Tau+/Aβ-), N = 9/4 for AD (P-Tau+/Aβ+), (a-c,e-g). One-sided ANOVA with Tukey’s post-hoc test (a-c), Mann-Whitney two-tailed t-test (e) and two-tailed Spearman’s rank non-parametric correlation test (g). Data are presented as the mean ± SEM.

Extended Data Fig. 2 RD3 and RD4 antibodies specificity.

Dot-blot assay to test the specificity of the antibodies raised against 3R tau (RD3, middle panel), 4R tau (RD4, right panel) isoforms of tau or secondary antibody only (left panel). blots is cropped; full gel pictures are shown in supplementary Fig. 2.

Extended Data Fig. 3 Presence of tau isoforms in hilar cells.

a, Confocal micrograph of 3R tau inclusions (red) in a non-astrocytic (s100β-) cell. b, Histogram showing the density of 3R tau inclusions in non-astrocytic cells of CTRL or AD patients. c, Confocal micrograph of 4R tau inclusions (red) in a non-astrocytic cell. d, Histogram showing the density of 4R tau inclusions in non-astrocytic cells. e, Confocal micrographs showing hilar astrocytes (green) that do not contain 3R tau inclusions (red, top panels) or do contain tau 3R inclusions (bottom panels, white arrows). f, Confocal micrographs showing hilar astrocytes (green) that do not contain 4R tau inclusions (red, top panels) or do contain tau 4R inclusions (bottom panels, white arrows). g, Confocal micrographs showing S100β+ astrocytes (green) in the hilus of CTRL and AD donors. h, Histogram showing the density of S100β+ astrocytes in the hilus of CTRL or AD patients. n = patients/sections per patient; N = 9/4 for Control, N = 6/4 for AD (P-Tau−/Aβ-), N = 6/4 for AD (P-Tau+/Aβ-), N = 8/4 for AD (P-Tau+/Aβ+), (b, d, h). One-sided ANOVA with Tukey’s post-hoc test. Data are presented as the mean ± SEM. Scale bars: 10 µm (a, c, e, f) 50 µm (g).

Extended Data Fig. 4 Synaptophysin expression in the hilus of patients.

a, Photomicrographs showing Synaptophysin immunostaining in the hilus of CTRL or AD donors. b, Histogram showing the intensity of Synaptophysin staining in CTRL or AD donors. c, Correlation plot between the intensity of Synaptophysin staining and the number of hilar astrocytes expressing 3R tau in AD patients. d, Correlation plot between the intensity of Synaptophysin staining and the number of hilar astrocytes expressing 4R tau in AD patients. N=patients/sections per patient; N = 9/4 for Control, N = 6/4 for AD (P-Tau−/Aβ-), N = 6/4 for AD (P-Tau+/Aβ-), N = 8/4 for AD (P-Tau+/Aβ+), (b-d). One-sided ANOVA with Tukey’s post-hoc test (b) and two-tailed Spearman’s rank non-parametric correlation test (c, d). Data are presented as the mean ± SEM. Scale bar: 25 µm.

Extended Data Fig. 5 LV-G1-GFP targets a small proportion of RGL stem cells of the dentate gyrus.

a, Confocal micrographs showing an astrocyte (left) and a Radial Glial-Like cell (RGL: right) that expressed GFP, 4 days after intrahippocampal injections of LV-G1-GFP. b, Histogram showing the proportion of infected cells (GFP+) that exhibited the morphology of astrocytes or RGL cells, 4, 14 and 120 days after intrahippocampal injections (dpi) of LV-G1-GFP. c, Confocal micrographs showing a RGL cell expressing GFP and GFAP (red), 4 days after intrahippocampal injections of LV-G1-GFP. Right panels: One channel view of the cell shown on the left panel. d, Histogram showing the proportion of RGL cells expressing GFP, 4, 14 and 120 days after intrahippocampal injections of LV-G1-GFP. N=animals/sections per animal; 4dpi: 6/5, 14dpi:6/5, 120dpi:6/5 (b-d). One-sided ANOVA with Tukey’s post-hoc test (d). Data are presented as the mean ± SEM. Scale bars: 10 µm (a), 50 µm (c).

Extended Data Fig. 6 Triple infection with LV-G1-CFP, LV-G1-1N3R and LV-G1-MitoTimer.

a, Confocal micrographs of the hilus, 120 days after intrahippocampal injections of LV-G1-GFP or LV-G1-1N3R+LV-G1-GFP or LV-G1-1N4R+LV-G1-GFP showing the co-localization of GFP or V5 (green) and tau MC-1 (red). b, Confocal micrograph showing the hilus of the dentate gyrus after infection with the 3 LVs. c, Higher magnification view of the astrocyte highlighted on (b). d, Three channel view of the same cell shown in (b). Scale bars: 10 µm (a), 25 µm (b), 5 µm (c,d).

Extended Data Fig. 7 In vitro targeting of astrocytes and morphological analyses.

a, Confocal micrographs of cultures infected with LV-G1-GFP showing the co-localization of GFP and GFAP (red, left panel), NeuN (red, middle panel) or Iba1 (red, right panel). b, Histogram showing the proportion of infected cells that co-expressed GFP with GFAP, Iba1 or NeuN, c, Confocal micrographs of cultures co-infected with LV-G1-GFP or LV-G1-1N3R+LV-G1-GFP or LV-G1-1N4R+LV-G1-GFP. d, Histogram showing the proportion of cells that were co-infected in the LV-G1-1N3R+LV-G1-GFP or LV-G1-1N4R+LV-G1-GFP conditions. e, Confocal micrographs of astrocytes after infection with LV-G1-GFP or LV-G1-1N3R+LV-G1-GFP or LV-G1-1N4R+LV-G1-GFP. Images are overlaid with a scaffold of the cell’s morphology. f-k, Violin graphs of the astrocytes’ (f) soma area, (g) total territory area, (h) total length of processes, (i) number of branching points, j, number of segments, (k) number of terminal points. N=cultures/cell per culture. (b): LV-G1-CFP: 4/203. (d): LV-G1-1N3R: 4/102 and LV-G1-1N3R: 4/97. (f): LV-G1-CFP: 4/70, LV-G1-1N3R: 4/81 and LV-G1-1N3R: 4/55. (g-k): LV-G1-CFP: 4/12, LV-G1-1N3R: 4/12 and LV-G1-1N3R: 4/12. Data are presented as the mean ± SEM. One-sided ANOVA with Tukey’s post-hoc test (b, f-k) and Mann-Whitney two-tailed t-test (d). Data are presented as the mean ± SEM. Scale bars: 50 µm (c), 20 µm (a, e).

Extended Data Fig. 8 3R tau accumulation in hilar astrocytes does not impact behaviors that are not related to spatial memory.

a, Schematic representation of the object recognition task. b, Histogram of the time spent interacting with the new and old object in animals infected with the LV-G1-GFP (white bars) or LV-G1-1N3R (yellow bars) LV. c, Histogram of the percentage of time spent interacting with the new object. d, Schematic representation of the dark/light box test. e, Histogram showing the time spent in each compartment. f, Schematic representation of the Y-maze. g, Histogram of the spontaneous alterations between each arm. h, Schematic representation of the contextual fear conditioning. (i) Histogram showing the percentage of freezing time before fear conditioning. j, Histogram showing the percentage of freezing time 24H after fear conditioning. LV-G1-CFP, N = 9 mice; LV-G1-1N3R, N = 12 mice. Data are presented as the mean ± SEM. Mann-Whitney two-tailed t-test (b, c, e, g, i, j), Wilcoxon signed-rank test to chance level with ### p < 0.001, ##p < 0.05, #p < 0.01 (c). Data are presented as the mean ± SEM.

Supplementary information

Supplementary Information

Supplementary Table 1 and Supplementary Figs. 1 and 2.

Reporting Summary

Supplementary Video 1

Example of time-lapse confocal movie showing an astrocyte (left) in a neuron/glial hippocampal co-culture, infected with both LV-G1-CFP (to label the cell; blue) and LV-G1-MitoTimer (to label mitochondria; white). Right: higher magnification movie showing mitochondrial dynamics in different regions of the astrocyte. Scale bar: 10 μm (left); 1 μm (right).

Supplementary Video 2

Example of time-lapse confocal movie showing an astrocyte in a neuron/glial hippocampal co-culture, infected with either LV-G1-CFP and LV-G1-MitoTimer (left) or LV-G1-CFP, LV-G1-1N3R and LV-G1-MitoTimer (right); scale bar: 10 μm.

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Richetin, K., Steullet, P., Pachoud, M. et al. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat Neurosci 23, 1567–1579 (2020). https://doi.org/10.1038/s41593-020-00728-x

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