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First-in-Rat Study of Human Alzheimer’s Disease Tau Propagation

  • Tomas Smolek
  • Santosh Jadhav
  • Veronika Brezovakova
  • Veronika Cubinkova
  • Bernadeta Valachova
  • Petr Novak
  • Norbert Zilka
Article

Abstract

One of the key features of misfolded tau in human neurodegenerative disorders is its propagation from one brain area into many others. In the last decade, in vivo tau spreading has been replicated in several mouse transgenic models expressing mutated human tau as well as in normal non-transgenic mice. In this study, we demonstrate for the first time that insoluble tau isolated from human AD brain induces full-blown neurofibrillary pathology in a sporadic rat model of tauopathy expressing non-mutated truncated tau protein. By using specific monoclonal antibodies, we were able to monitor the spreading of tau isolated from human brain directly in the rat hippocampus. We found that exogenous human AD tau was able to spread from the area of injection and induce tau pathology. Interestingly, solubilisation of insoluble AD tau completely abolished the capability of tau protein to induce and spread of neurofibrillary pathology in the rat brain. Our results show that exogenous tau is able to induce and drive neurofibrillary pathology in rat model for human tauopathy in a similar way as it was described in various mouse transgenic models. Rat tau spreading model has many advantages over mouse and other organisms including size and complexity, and thus is highly suitable for identification of pathogenic mechanism of tau spreading.

Keywords

Tau spreading Alzheimer’s disease Tau strains Neurofibrillary tangles Prion-like spreading 

Notes

Acknowledgements

The authors wish to thank to the brain banks from Newcastle, London and Kuopio for providing the brain tissues.

Funding

The work is supported by research grants JPND ReFRAME, EU structural fund 26240220046, APVV-14-0872, VEGA 2/0164/16 and 2/0181/17, and Axon Neuroscience R&D Services SE.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary material

12035_2018_1102_Fig7_ESM.gif (44 kb)
Figure 1

Formation of neurofibrillary tangles in AD-tau injected animals is a dose dependent process. Immunomicrographs showing AT8 positive tangles after injection of 600 ng (a,d) or 400 ng (d-e) of AD-tau at both the injected (a-b) and non-injected side (d-e). Graphs showing number of AT8 positive tangles in injected side (c) or non‑injected side (f). Statistical analysis revealed significantly higher level of tangles after injection of 600 ng of AD-tau in injected site. Paired t-test, p values: *p < 0.05. (GIF 44 kb)

12035_2018_1102_MOESM1_ESM.tif (1.7 mb)
High resolution image (TIF 1757 kb)
12035_2018_1102_MOESM2_ESM.jpg (248 kb)
Figure 2 Comparison of immunoblot and Ponceau for control of loading of insoluble tau extract. a. Immunoblotting of insoluble tau extracts isolated from control (Ctrl) and AD-tau injected (AD-tau 1,2,3) groups using pan-tau antibody DC25 shows higher levels of DC25 immuno-positivity in the AD-tau injected group. However, no change in protein levels is observed by ponceau staining (b). Sarkosyl insoluble tau extract from brainstem of transgenic rat model expressing human truncated tau (+ve) and PHF-tau were used as controls. (JPG 248 kb)

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Authors and Affiliations

  1. 1.Institute of Neuroimmunology, Slovak Academy of Sciences, Centre of Excellence for Alzheimer’s Disease and Related DisordersBratislavaSlovak Republic
  2. 2.Axon Neuroscience R&D Services SEBratislavaSlovak Republic
  3. 3.Axon Neuroscience CRM Services SEBratislavaSlovak Republic

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