Article | Published:

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

Nature Medicine volume 24, pages 2938 (2018) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

  2. 2.

    et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24 (1997).

  3. 3.

    , , , & Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch. Neurol. 61, 378–384 (2004).

  4. 4.

    , , & Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

  5. 5.

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

  6. 6.

    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).

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 10.

    , , & Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).

  11. 11.

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

  12. 12.

    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).

  13. 13.

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

  14. 14.

    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).

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    et al. Single App knock-in mouse models of Alzheimer's disease. Nat. Neurosci. 17, 661–663 (2014).

  19. 19.

    , & Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).

  20. 20.

    & 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).

  21. 21.

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

  22. 22.

    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).

  23. 23.

    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).

  24. 24.

    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).

  25. 25.

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

  26. 26.

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

  27. 27.

    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).

  28. 28.

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

  29. 29.

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

  30. 30.

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

  31. 31.

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

  32. 32.

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

  33. 33.

    , & β-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin–proteasome system. J. Neurosci. 26, 4277–4288 (2006).

  34. 34.

    et al. Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease. Alzheimers Dement. 12, 164–169 (2016).

  35. 35.

    & Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry 45, 15692–15701 (2006).

  36. 36.

    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).

  37. 37.

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

  38. 38.

    , , , & 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).

  39. 39.

    & Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months. Physiol. Behav. 75, 627–642 (2002).

Download references


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


  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


  1. Search for Zhuohao He in:

  2. Search for Jing L Guo in:

  3. Search for Jennifer D McBride in:

  4. Search for Sneha Narasimhan in:

  5. Search for Hyesung Kim in:

  6. Search for Lakshmi Changolkar in:

  7. Search for Bin Zhang in:

  8. Search for Ronald J Gathagan in:

  9. Search for Cuiyong Yue in:

  10. Search for Christopher Dengler in:

  11. Search for Anna Stieber in:

  12. Search for Magdalena Nitla in:

  13. Search for Douglas A Coulter in:

  14. Search for Ted Abel in:

  15. Search for Kurt R Brunden in:

  16. Search for John Q Trojanowski in:

  17. Search for Virginia M-Y Lee in:


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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Virginia M-Y Lee.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures & Tables

    Supplementary Figures 1–11 & Supplementary Tables 1–3

  2. 2.

    Life Sciences Reporting Summary

About this article

Publication history





Further reading