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Human subiculo-fornico-mamillary system in Alzheimer’s disease: Tau seeding by the pillar of the fornix

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Abstract

In Alzheimer’s disease (AD), Tau and Aβ aggregates involve sequentially connected regions, sometimes distantly separated. These alterations were studied in the pillar of the fornix (PoF), an axonal tract, to analyse the role of axons in their propagation. The PoF axons mainly originate from the subicular neurons and project to the mamillary body. Forty-seven post-mortem cases at various Braak stages (Tau) and Thal phases (Aβ) were analysed by immunohistochemistry. The distribution of the lesions showed that the subiculum was affected before the mamillary body, but neither Tau aggregation nor Aβ deposition was consistently first. The subiculum and the mamillary body contained Gallyas positive neurofibrillary tangles, immunolabelled by AT8, TG3, PHF1, Alz50 and C3 Tau antibodies. In the PoF, only thin and fragmented threads were observed, exclusively in the cases with neurofibrillary tangles in the subiculum. The threads were made of Gallyas negative, AT8 and TG3 positive Tau. They were intra-axonal and devoid of paired helical filaments at electron microscopy. We tested PoF homogenates containing Tau AT8 positive axons in a Tau P301S biosensor HEK cell line and found a seeding activity. There was no Aβ immunoreactivity detected in the PoF. We could follow microcryodissected AT8 positive axons entering the mamillary body; contacts between Tau positive endings and Aβ positive diffuse or focal deposits were observed in CLARITY-cleared mamillary body. In conclusion, we show that non-fibrillary, hyperphosphorylated Tau is transported by the axons of the PoF from the subiculum to the mamillary body and has a seeding activity. Either Tau aggregation or Aβ accumulation may occur first in this system: this inconstant order is incompatible with a cause-and-effects relationship. However, both pathologies were correlated and intimately associated, indicating an interaction of the two processes, once initiated.

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Acknowledgements

This project received financial support from France Alzheimer (project “Propagation of Tau and Aβ aggregation through axons in the subiculo-fornico-mamillary system: tracking propagons” and Ibisa (Project “Neuro-CEB better”). Manon Thierry was funded by a doctoral scholarship from the Ministry of Research and Higher Education, attributed by the doctoral school “Physiology, Physiopathology and Therapeutics-ED394” (Sorbonne University). The human samples were obtained from the Neuro-CEB brain bank (BRIF Number 0033-00011), partly funded by the patients’ associations ARSEP, ARSLA, “Connaître les Syndromes Cérébelleux”, France-DFT, France Parkinson and by Vaincre Alzheimer Fondation, to which we express our gratitude. We are also grateful to the patients and their families. We thank Sabrina Leclère-Turbant and Marie-Claire Artaud for their technical and managerial assistance with post-mortem human samples. The brain bank is hosted by the Biological Resources Platform of Pitié-Salpêtrière Hospital, APHP. Brain clarification with CLARITY was performed on the ICM HISTOMICS platform. Cell culture experiments were performed on the ICM CELIS platform. Biphoton, confocal and electronic microscopy pictures were acquired on the ICM.QUANT imaging platform. We thank the technical team of the Raymond Escourolle neuropathology department as well as the technical staff involved at ICM, including Valérie Thuries and Annick Prigent for their help and technical advices in histology, Julien Dumont for his assistance and expertise in CLARITY-cleared tissue imaging and analysis and Dominique Langui and Asha Baskaran for their help and knowledge in electron microscopy analysis. We also thank Jean-Pierre Brion and Kunie Ando for their valuable advices and discussion. The Neuro-CEB Neuropathology network includes: Dr. Franck Letournel (CHU Angers), Dr. Marie-Laure Martin-Négrier (CHU Bordeaux), Pr. Françoise Chapon (CHU Caen), Pr. Catherine Godfraind (CHU Clermont-Ferrand), Pr. Claude-Alain Maurage (CHU Lille), Dr. Vincent Deramecourt (CHU Lille), Dr. David Meyronnet (CHU Lyon), Dr. Nathalie Streichenberger (CHU Lyon), Dr. André Maues de Paula (CHU Marseille), Pr. Valérie Rigau (CHU Montpellier), Dr. Fanny Vandenbos-Burel (Nice), Pr. Charles Duyckaerts (CHU PS Paris), Pr. Danielle Seilhean (CHU PS, Paris), Dr. Susana Boluda (CHU PS, Paris), Dr. Isabelle Plu (CHU PS, Paris), Dr. Serge Milin (CHU Poitiers), Dr. Dan Christian Chiforeanu (CHU Rennes), Pr. Annie Laquerrière (CHU Rouen), Dr. Béatrice Lannes (CHU Strasbourg).

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Authors and Affiliations

  1. Alzheimer’s and Prion Diseases Team, Paris Brain Institute, CNRS, UMR 7225, INSERM 1127, Sorbonne University UM75, Paris, France

    Manon Thierry, Susana Boluda, Benoît Delatour, Serge Marty, Marie-Claude Potier & Charles Duyckaerts

  2. Laboratoire de Neuropathologie Raymond Escourolle, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, 47, Blvd de l’Hôpital, 75651, Paris Cedex 13, France

    Manon Thierry, Susana Boluda, Danielle Seilhean & Charles Duyckaerts

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Brainbank Neuro-CEB Neuropathology Network

  • Franck Letournel
  • , Marie-Laure Martin-Négrier
  • , Françoise Chapon
  • , Catherine Godfraind
  • , Claude-Alain Maurage
  • , Vincent Deramecourt
  • , David Meyronnet
  • , Nathalie Streichenberger
  • , André Maues de Paula
  • , Valérie Rigau
  • , Fanny Vandenbos-Burel
  • , Charles Duyckaerts
  • , Danielle Seilhean
  • , Susana Boluda
  • , Isabelle Plu
  • , Serge Milin
  • , Dan Christian Chiforeanu
  • , Annie Laquerrière
  •  & Béatrice Lannes

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Correspondence to Charles Duyckaerts.

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The members of Brainbank Neuro-CEB Neuropathology Network are listed in the Acknowledgements section.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2019_2108_MOESM1_ESM.avi

Supplementary material 1 (AVI 35884 kb) Video 1 (online resource) CLARITY in the mamillary body showing Aβ diffuse deposit surrounded by Tau positive neurites in three dimensions. Human brain, anti-Aβ 4G8/Tau B19 immunohistochemistry, Aβ in green (Alexa 488), Tau in red (Alexa 555)

401_2019_2108_MOESM2_ESM.avi

Supplementary material 2 (AVI 31367 kb) Video 2 (online resource) CLARITY in the mamillary body. Aβ neuritic deposit surrounded by Tau positive neurites in three dimensions. Human brain, anti-Aβ 4G8/Tau B19 immunohistochemistry, Aβ in green (Alexa 488), Tau in red (Alexa 555)

401_2019_2108_MOESM3_ESM.avi

Supplementary material 3 (AVI 137117 kb) Video 3 (online resource) General view of the fornix ending in the mamillary body where Tau and Aβ pathologies converged. Three-dimensional view after CLARITY. Human brain, anti-Aβ 4G8/Tau B19 immunohistochemistry, Aβ in green (Alexa 488), Tau in red (Alexa 555)

Supplementary material 4 (DOCX 23 kb) Primary antibodies and immunohistochemistry protocols

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Supplementary material 5 (TIFF 43880 kb) Supplementary Fig. 1 (online resource) Aβ volume densities in the subiculo-fornico-mamillary system. Each case is represented by a dot (values obtained in the subiculum), square (values obtained in the pillar of the fornix) and triangle (values obtained in the mamillary body). The volume densities of Aβ deposits (or amyloid loads) are represented as a function of Braak stages (Kruskal–Wallis and Dunn’s post tests in comparison with the control group, which included cases at Braak stages 0/I/II, *** p < 0.001, **** p < 0.0001). Error bars: standard error of the mean

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Supplementary material 6 (TIFF 214293 kb) Supplementary Fig. 2 (online resource) Relationship between Tau pathology in the various regions of the subiculo-fornico-mamillary system. a “Observed”: the severity of Tau lesions was graded 0 to 3. The three contingency tables show the number of cases corresponding to the observed association of grades between the two areas represented on the X and Y axes. b “Observed–Expected”. “Expected” means expected number in the case of a random distribution: it is the product of the total number of cases in the corresponding row, times the total number in the corresponding column divided by the total number of cases (as in a Chi²). The difference between the “Observed” and “Expected” numbers of cases is shown in Table b. A positive difference indicates an excess of the observed number of cases, in comparison with a random distribution and conversely. The cells containing too many observed cases (by comparison with the expected number) are coloured in red tones and the ones containing too few in green tones. The distribution of the enriched cells (coloured in red) located along a diagonal or parallel to it in all tables, suggests correlations of Tau pathology severities between the various regions of the subiculo-fornico-mamillary system. c Linear regressions of Tau lesion severities, between each region of the subiculo-fornico-mamillary system. The computation is made under the hypothesis that the semi-quantitative scores of Tau pathology approximately describe a continuous gradient of severity: under this hypothesis, intermediate values may be interpolated by the regression line. Pearson’s r and p-value are indicated in red. The diameter of the dots is proportional to the number of corresponding cases (as indicated in the figure). The equations of the regression lines are: Tau grade in the pillar of the fornix = 0.9921 × Tau grade in the subiculum + 0.2661. Tau grade in the mamillary body = 0.5241 × Tau grade in the pillar of the fornix − 0.1144. Tau grade in the mamillary body = 0.5499 × Tau grade in the subiculum − 0.0109

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Supplementary material 7 (TIFF 144922 kb) Supplementary Fig. 3 (online resource) Scatterplots showing the linear regressions of the volume densities of Aβ pathology (Y-axis) as a function of the semi-quantitative scores of Tau pathology (X-axis) between each region of the subiculo-fornico-mamillary system. As in Supplementary Fig. 2, we postulated that the semi-quantitative scores of Tau pathology approximated a continuous gradient of severity and that the intermediate values were interpolated by the regression line. Pearson’s r and p-value are indicated in red

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Thierry, M., Boluda, S., Delatour, B. et al. Human subiculo-fornico-mamillary system in Alzheimer’s disease: Tau seeding by the pillar of the fornix. Acta Neuropathol 139, 443–461 (2020). https://doi.org/10.1007/s00401-019-02108-7

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