Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Hardy, J.A. & Higgins, G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    Article  CAS  Google Scholar 

  2. Gómez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24 (1997).

    Article  Google Scholar 

  3. Bennett, D.A., Schneider, J.A., Wilson, R.S., Bienias, J.L. & Arnold, S.E. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch. Neurol. 61, 378–384 (2004).

    Article  Google Scholar 

  4. Braak, H., Thal, D.R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

    Article  CAS  Google Scholar 

  5. Schöll, M. et al. PET imaging of tau deposition in the aging human brain. Neuron 89, 971–982 (2016).

    Article  Google Scholar 

  6. Schwarz, A.J. et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139, 1539–1550 (2016).

    Article  Google Scholar 

  7. Sepulcre, J. et al. In vivo tau, amyloid, and gray matter profiles in the aging brain. J. Neurosci. 36, 7364–7374 (2016).

    Article  CAS  Google Scholar 

  8. Brier, M.R. et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci. Transl. Med. 8, 338ra66 (2016).

    Article  Google Scholar 

  9. Wang, L. et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy. JAMA Neurol. 73, 1070–1077 (2016).

    Article  Google Scholar 

  10. Götz, J., Chen, F., van Dorpe, J. & Nitsch, R.M. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).

    Article  Google Scholar 

  11. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

    Article  CAS  Google Scholar 

  12. Bolmont, T. et al. Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP × Tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).

    Article  CAS  Google Scholar 

  13. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    Article  CAS  Google Scholar 

  14. Hurtado, D.E. et al. Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am. J. Pathol. 177, 1977–1988 (2010).

    Article  CAS  Google Scholar 

  15. Pooler, A.M. et al. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathol. Commun. 3, 14 (2015).

    Article  Google Scholar 

  16. Bennett, R.E. et al. Enhanced tau aggregation in the presence of amyloid β. Am. J. Pathol. 187, 1601–1612 (2017).

    Article  CAS  Google Scholar 

  17. Guo, J.L. et al. Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J. Exp. Med. 213, 2635–2654 (2016).

    Article  CAS  Google Scholar 

  18. Saito, T. et al. Single App knock-in mouse models of Alzheimer's disease. Nat. Neurosci. 17, 661–663 (2014).

    Article  CAS  Google Scholar 

  19. Nelson, P.T., Braak, H. & Markesbery, W.R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).

    Article  CAS  Google Scholar 

  20. Mann, D.M. & Esiri, M.M. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J. Neurol. Sci. 89, 169–179 (1989).

    Article  CAS  Google Scholar 

  21. Crary, J.F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).

    Article  CAS  Google Scholar 

  22. Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    Article  CAS  Google Scholar 

  23. Sadleir, K.R. et al. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease. Acta Neuropathol. 132, 235–256 (2016).

    Article  CAS  Google Scholar 

  24. Montine, T.J. et al. National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 123, 1–11 (2012).

    Article  CAS  Google Scholar 

  25. Bannerman, D.M. et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 28, 273–283 (2004).

    Article  CAS  Google Scholar 

  26. Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

    Article  CAS  Google Scholar 

  27. Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

    Article  CAS  Google Scholar 

  28. Meyer-Luehmann, M. et al. Extracellular amyloid formation and associated pathology in neural grafts. Nat. Neurosci. 6, 370–377 (2003).

    Article  CAS  Google Scholar 

  29. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  CAS  Google Scholar 

  30. Eisele, Y.S. et al. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330, 980–982 (2010).

    Article  CAS  Google Scholar 

  31. Langer, F. et al. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J. Neurosci. 31, 14488–14495 (2011).

    Article  CAS  Google Scholar 

  32. Rosen, R.F. et al. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J. Neurochem. 120, 660–666 (2012).

    Article  CAS  Google Scholar 

  33. Almeida, C.G., Takahashi, R.H. & Gouras, G.K. β-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin–proteasome system. J. Neurosci. 26, 4277–4288 (2006).

    Article  CAS  Google Scholar 

  34. Montine, T.J. et al. Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease. Alzheimers Dement. 12, 164–169 (2016).

    Article  Google Scholar 

  35. Li, W. & Lee, V.M. Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry 45, 15692–15701 (2006).

    Article  CAS  Google Scholar 

  36. Iba, M. et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J. Neurosci. 33, 1024–1037 (2013).

    Article  CAS  Google Scholar 

  37. Guo, J.L. & Lee, V.M. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).

    Article  CAS  Google Scholar 

  38. Lee, E.B., Skovronsky, D.M., Abtahian, F., Doms, R.W. & Lee, V.M. Secretion and intracellular generation of truncated Aβ in β-site amyloid-β precursor protein–cleaving enzyme expressing human neurons. J. Biol. Chem. 278, 4458–4466 (2003).

    Article  CAS  Google Scholar 

  39. King, D.L. & Arendash, G.W. Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months. Physiol. Behav. 75, 627–642 (2002).

    Article  CAS  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Virginia M-Y Lee.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures & Tables

Supplementary Figures 1–11 & Supplementary Tables 1–3 (PDF 11193 kb)

Life Sciences Reporting Summary (PDF 159 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4443

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing