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Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation

Nature Medicine volume 24, pages 29–38 (2018)Cite this article

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Abstract

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) plaques and intracellular tau inclusions. However, the exact mechanistic link between these two AD lesions remains enigmatic. Through injection of human AD-brain-derived pathological tau (AD-tau) into Aβ plaque–bearing mouse models that do not overexpress tau, we recapitulated the formation of three major types of AD-relevant tau pathologies: tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau), AD-like neurofibrillary tangles (NFTs) and neuropil threads (NTs). These distinct tau pathologies have different temporal onsets and functional consequences on neural activity and behavior. Notably, we found that Aβ plaques created a unique environment that facilitated the rapid amplification of proteopathic AD-tau seeds into large tau aggregates, initially appearing as NP tau, which was followed by the formation and spread of NFTs and NTs, likely through secondary seeding events. Our study provides insights into a new multistep mechanism underlying Aβ plaque–associated tau pathogenesis.

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Figure 1: Aβ plaques facilitate AD-tau induction of NP tau, rather than NFTs, at early seeding stages.
Figure 2: NP tau aggregates faster and spreads more widely than NFT tau.
Figure 3: Mislocalized tau in periplaque dystrophic axons is critical for AD-tau-induced NP tau aggregation.
Figure 4: NP tau triggers the formation of NFTs and NTs through secondary seeding events at later seeding stages.
Figure 5: NP tau appears earlier than NFTs in human AD brain.
Figure 6: The induced tau pathologies elicit effects on neural circuit activity and mouse behaviors.

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Acknowledgements

We thank S. Kim, B. Zoll, H. Brown, F. Bassil, J. Robinson, T. Schuck and M. Byrne for technical assistance. We thank W. O'Brien and the Penn Neurobehavioral Testing Core for help with behavior tests, S. Xie for help with statistical analyses and E. Lee for helpful comments. We thank N. Kanaan (Michigan State University) for providing TOC1 antibody, which was generated and initially provided by L. Binder (deceased), P. Davies (Hofstra Northwell School of Medicine) for contributing PHF1, MC1 and TG3 antibodies, and M. Goedert (University of Cambridge) for contributing pS422 antibody. T. Saido (RIKEN Brain Science Institute) is thanked for providing APP-KI mice. This work was funded by National Institute on Aging (NIA) AG10124 (J.Q.T.), AG17586 (V.M.-Y.L.), AG017628 (T.A.), CurePSP (J.Q.T.) and the Woods Foundation (V.M.-Y.L.).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Zhuohao He, Jing L Guo, Jennifer D McBride, Sneha Narasimhan, Hyesung Kim, Lakshmi Changolkar, Bin Zhang, Ronald J Gathagan, Anna Stieber, Magdalena Nitla, Kurt R Brunden, John Q Trojanowski & Virginia M-Y Lee

  2. Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Cuiyong Yue, Christopher Dengler & Douglas A Coulter

  3. Departments of Neuroscience and of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Douglas A Coulter

  4. Iowa Neuroscience Institute and Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

    Ted Abel

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  1. Zhuohao He
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Contributions

Z.H. designed the studies with the help of J.L.G., generated most of the data along with J.D.M. and interpreted all the results. J.L.G. and L.C. purified brain lysates for injection. S.N. provided the data of AD-WT mice at 9 m.p.i., and H.K. did the manual quantification for NIs and NP tau. B.Z. and R.J.G. performed mouse brain injection surgeries, A.S. did the immuno-EM and M.N. bred 5xFAD mice. C.Y., C.D. and D.A.C. performed neural circuit recording. K.R.B. and J.Q.T. participated in discussion of results and design of some experiments, as well as in writing of the manuscript. T.A. participated in experimental design and interpreting behavior results. Z.H. and V.M.-Y.L. wrote the manuscript, and all coauthors read and approved the manuscript. V.M.-Y.L. supervised the study.

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Correspondence to Virginia M-Y Lee.

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He, Z., Guo, J., McBride, J. et al. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24, 29–38 (2018). https://doi.org/10.1038/nm.4443

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