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.

  • Review Article
  • Published:

Synergy between amyloid-β and tau in Alzheimer’s disease

Nature Neuroscience volume 23, pages 1183–1193 (2020)Cite this article

Subjects

Abstract

Patients with Alzheimer’s disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this ‘triggering’ function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ–tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Aβ plaques accelerate tau spreading and cognitive decline in human AD.
Fig. 2: The interaction between Aβ and tau enhances neural circuit impairment.
Fig. 3: Microglia may be critical intermediaries of Aβ–tau synergy.
Fig. 4: Aβ and tau pathways may converge at the level of gene expression.

Similar content being viewed by others

Data availability statement

Data sharing not applicable to this review article as no data sets were generated.

References

  1. Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Ingelsson, M. et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–931 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Lleó, A., Berezovska, O., Growdon, J. H. & Hyman, B. T. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am. J. Geriatr. Psychiatry 12, 146–156 (2004).

    Article  PubMed  Google Scholar 

  4. Ryan, N. S. et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 15, 1326–1335 (2016).

    Article  PubMed  Google Scholar 

  5. Hyman, B. T. Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 68, 1062–1064 (2011).

    Article  PubMed  Google Scholar 

  6. Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lee, H. K. et al. Three dimensional human neuro-spheroid model of Alzheimer’s disease based on differentiated induced pluripotent stem cells. PLoS One 11, e0163072 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oddo, S. et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Maia, L. F. et al. Changes in amyloid-β and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013).

    Article  PubMed  CAS  Google Scholar 

  11. Schelle, J. et al. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. 13, 701–709 (2017).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat. Neurosci. 22, 57–64 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Villeneuve, S. et al. Existing Pittsburgh compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain 138, 2020–2033 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. J. Am. Med. Assoc. 313, 1924–1938 (2015).

    Article  Google Scholar 

  17. 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  PubMed  PubMed Central  Google Scholar 

  18. Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19, 687–700 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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  PubMed  Google Scholar 

  20. Jucker, M. & Walker, L. C. Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. Nat. Neurosci. 21, 1341–1349 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peng, C., Trojanowski, J. Q. & Lee, V. M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Pontecorvo, M. J. et al. Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 140, 748–763 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Adams, J. N., Maass, A., Harrison, T. M., Baker, S. L. & Jagust, W. J. Cortical tau deposition follows patterns of entorhinal functional connectivity in aging. eLife 8, e49132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jacobs, H. I. L. et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat. Neurosci. 21, 424–431 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sperling, R. A. et al. The impact of amyloid-beta and tau on prospective cognitive decline in older individuals. Ann. Neurol. 85, 181–193 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hanseeuw, B. J. et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 76, 915–924 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  27. Timmers, M. et al. Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer’s disease. Neurobiol. Aging 79, 131–141 (2019).

    Article  PubMed  Google Scholar 

  28. Hanseeuw, B. J. et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann. Neurol. 81, 583–596 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pascoal, T. A. et al. Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol. Psychiatry 22, 306–311 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. 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  PubMed  PubMed Central  Google Scholar 

  31. Desikan, R. S. et al. Amyloid-β associated volume loss occurs only in the presence of phospho-tau. Ann. Neurol. 70, 657–661 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fortea, J. et al. Cerebrospinal fluid β-amyloid and phospho-tau biomarker interactions affecting brain structure in preclinical Alzheimer disease. Ann. Neurol. 76, 223–230 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat. Commun. 6, 8490 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sepulcre, J. et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat. Med. 24, 1910–1918 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ferrari, A., Hoerndli, F., Baechi, T., Nitsch, R. M. & Götz, J. beta-Amyloid induces paired helical filament-like tau filaments in tissue culture. J. Biol. Chem. 278, 40162–40168 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491–1495 (2001).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vergara, C. et al. Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol. 137, 397–412 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  PubMed Central  CAS  Google Scholar 

  44. Gomes, L. A. et al. Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol. 138, 913–941 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Jackson, R. J. et al. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer’s disease. Eur. J. Neurosci. 44, 3056–3066 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ribé, E. M. et al. Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice. Neurobiol. Dis. 20, 814–822 (2005).

    Article  PubMed  CAS  Google Scholar 

  47. Chen, W. et al. Increased tauopathy drives microglia-mediated clearance of beta-amyloid. Acta Neuropathol. Commun. 4, 63 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17, 777–792 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zott, B. et al. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science 365, 559–565 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Roberson, E. D. et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31, 700–711 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Marinković, P. et al. In vivo imaging reveals reduced activity of neuronal circuits in a mouse tauopathy model. Brain 142, 1051–1062 (2019).

    Article  PubMed  Google Scholar 

  54. Menkes-Caspi, N. et al. Pathological tau disrupts ongoing network activity. Neuron 85, 959–966 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. McInnes, J. et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by tau. Neuron 97, 823–835.e8 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Hatch, R. J., Wei, Y., Xia, D. & Götz, J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 133, 717–730 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tracy, T. E. et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Warmus, B. A. et al. Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia. J. Neurosci. 34, 16482–16495 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology. Nat. Neurosci. 22, 47–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Sierksma, A. et al. Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to tau pathology. EMBO Mol. Med. 12, e10606 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pickett, E. K. et al. Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer’s disease. Cell Reports 29, 3592–3604.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Ke, Y. D. et al. CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation. J. Biol. Chem. 294, 14149–14162 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Evans, H. T., Benetatos, J., van Roijen, M., Bodea, L. G. & Götz, J. Decreased synthesis of ribosomal proteins in tauopathy revealed by non-canonical amino acid labelling. EMBO J. 38, e101174 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Kuchibhotla, K. V. et al. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc. Natl. Acad. Sci. USA 111, 510–514 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Huijbers, W. et al. Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. J. Neurosci. 39, 548–556 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sohn, P. D. et al. Pathogenic tau impairs axon initial segment plasticity and excitability homeostasis. Neuron 104, 458–470.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Das, M. et al. Neuronal levels and sequence of tau modulate the power of brain rhythms. Neurobiol. Dis. 117, 181–188 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. DeVos, S. L. et al. Tau reduction in the presence of amyloid-β prevents tau pathology and neuronal death in vivo. Brain 141, 2194–2212 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Angulo, S. L. et al. Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit. Neurobiol. Dis. 108, 261–276 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Green, C. et al. Functional networks are impaired by elevated tau-protein but reversible in a regulatable Alzheimer’s disease mouse model. Mol. Neurodegener. 14, 13 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Schultz, A. P. et al. Phases of hyperconnectivity and hypoconnectivity in the default mode and salience networks track with amyloid and tau in clinically normal individuals. J. Neurosci. 37, 4323–4331 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ondrejcak, T. et al. Soluble tau aggregates inhibit synaptic long-term depression and amyloid β-facilitated LTD in vivo. Neurobiol. Dis. 127, 582–590 (2019).

    Article  CAS  PubMed  Google Scholar 

  73. Chabrier, M. A., Cheng, D., Castello, N. A., Green, K. N. & LaFerla, F. M. Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol. Dis. 64, 107–117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Umeda, T. et al. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol. 127, 685–698 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Vossel, K. A. et al. Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β. J. Cell Biol. 209, 419–433 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ittner, L. M. et al. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc. Natl. Acad. Sci. USA 105, 15997–16002 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fang, E. F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Manczak, M. & Reddy, P. H. Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum. Mol. Genet. 21, 5131–5146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pérez, M. J., Vergara-Pulgar, K., Jara, C., Cabezas-Opazo, F. & Quintanilla, R. A. Caspase-cleaved tau impairs mitochondrial dynamics in Alzheimer’s disease. Mol. Neurobiol. 55, 1004–1018 (2018).

    Article  PubMed  CAS  Google Scholar 

  80. Adalbert, R. et al. Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport. Neurobiol. Aging 68, 68–75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rhein, V. et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc. Natl. Acad. Sci. USA 106, 20057–20062 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lippi, S. L. P., Smith, M. L. & Flinn, J. M. A novel hAPP/htau mouse model of Alzheimer’s disease: inclusion of APP with tau exacerbates behavioral deficits and zinc administration heightens tangle pathology. Front. Aging Neurosci. 10, 382 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang, C., Saar, V., Leung, K. L., Chen, L. & Wong, G. Human amyloid β peptide and tau co-expression impairs behavior and causes specific gene expression changes in Caenorhabditis elegans. Neurobiol. Dis. 109, 88–101 (2018). Pt A.

    Article  CAS  PubMed  Google Scholar 

  84. Benbow, S. J., Strovas, T. J., Darvas, M., Saxton, A. & Kraemer, B. C. Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic C. elegans. Hum. Mol. Genet. 29, 495–505 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Guerrero-Muoz, M. J., Jackson, G. R. & Kayed, R. Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49, 10039–10041 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Vasconcelos, B. et al. Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol. 131, 549–569 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Griner, S. L. et al. Structure-based inhibitors of amyloid beta core suggest a common interface with tau. eLife 8, e46924 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Ittner, A. et al. Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science 354, 904–908 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Manczak, M. & Reddy, P. H. Abnormal interaction of oligomeric amyloid-β with phosphorylated tau: implications to synaptic dysfunction and neuronal damage. J. Alzheimers Dis. 36, 285–295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Prinz, M., Jung, S. & Priller, J. Microglia biology: one century of evolving concepts. Cell 179, 292–311 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Maphis, N. et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138, 1738–1755 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Mancuso, R. et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142, 3243–3264 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bolós, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016).

    Article  PubMed  CAS  Google Scholar 

  97. Hopp, S. C. et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J. Neuroinflammation 15, 269 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Cserép, C. et al. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science 367, 528–537 (2020).

    Article  PubMed  CAS  Google Scholar 

  99. Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Martini-Stoica, H. et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 215, 2355–2377 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Tai, X. Y. et al. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. Brain 139, 2441–2455 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat. Neurosci. 19, 1085–1092 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schultz, M. K. Jr. et al. Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice. Neurobiol. Dis. 118, 161–176 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Rodriguez, G.A., Barrett, G.M., Duff, K.E. & Hussaini, S.A. Attenuation of entorhinal cortex hyperactivity reduces Aβ and tau pathology. Preprint at bioRxiv https://doi.org/10.1101/487405 (2019).

  108. Yap, E. L. & Greenberg, M. E. Activity-regulated transcription: bridging the gap between neural activity and behavior. Neuron 100, 330–348 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bezprozvanny, I. & Mattson, M. P. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31, 454–463 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Therriault, J. et al. APOEε4 potentiates the relationship between amyloid-β and tau pathologies. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0688-6 (2020).

  111. Kounnas, M. Z. et al. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82, 331–340 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bassil, F. et al. Amyloid-Beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of lewy body disorders with Aβ pathology. Neuron 105, 260–275.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Guo, J. L. et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Corbett, G. T. et al. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 139, 503–526 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, F. et al. β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aay6931 (2020).

  117. Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Senatorov, V.V. Jr. et al. Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaw8283 (2019).

  119. Milikovsky, D.Z. et al. Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaw8954 (2019).

  120. Sun, W., Samimi, H., Gamez, M., Zare, H. & Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21, 1038–1048 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Eftekharzadeh, B. et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99, 925–940.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Rasool, S., Martinez-Coria, H., Wu, J. W., LaFerla, F. & Glabe, C. G. Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice. J. Neurochem. 126, 473–482 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Rosenberg, R. N., Fu, M. & Lambracht-Washington, D. Active full-length DNA Aβ42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. Alzheimers Res. Ther. 10, 115 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Saito, T. et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J. Biol. Chem. 294, 12754–12765 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gamache, J. et al. Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat. Commun. 10, 2479 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Iturria-Medina, Y., Sotero, R. C., Toussaint, P. J., Mateos-Pérez, J. M. & Evans, A. C. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat. Commun. 7, 11934 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang, X. et al. Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-β oligomerization in rats. J. Alzheimers Dis. 21, 813–822 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Kitaguchi, H. et al. Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain Res. 1294, 202–210 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Qiu, L. et al. Chronic cerebral hypoperfusion enhances tau hyperphosphorylation and reduces autophagy in Alzheimer’s disease mice. Sci. Rep. 6, 23964 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Nortley, R. et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 365, eaav9518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Merlini, M., Wanner, D. & Nitsch, R. M. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer’s disease-related microvascular cerebral amyloid angiopathy. Acta Neuropathol. 131, 737–752 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bennett, R. E. et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 115, E1289–E1298 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Blair, L. J. et al. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol. Commun. 3, 8 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Sagare, A. P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).

    Article  PubMed  CAS  Google Scholar 

  136. Nation, D. A. et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 25, 270–276 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Duan, L. et al. PDGFRβ cells rapidly relay inflammatory signal from the circulatory system to neurons via chemokine CCL2. Neuron 100, 183–200.e8 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Pluvinage, J. V. & Wyss-Coray, T. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nat. Rev. Neurosci. 21, 93–102 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Rabin, J. S. et al. Vascular risk and β-amyloid are synergistically associated with cortical tau. Ann. Neurol. 85, 272–279 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).

    Article  PubMed  Google Scholar 

  142. Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Suberbielle, E. et al. Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci. 16, 613–621 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sykora, P. et al. DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res. 43, 943–959 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Bodea, L. G. et al. Accelerated aging exacerbates a pre-existing pathology in a tau transgenic mouse model. Aging Cell 16, 377–386 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zullo, J. M. et al. Regulation of lifespan by neural excitation and REST. Nature 574, 359–364 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Brawek, B. et al. Impairment of in vivo calcium signaling in amyloid plaque-associated microglia. Acta Neuropathol. 127, 495–505 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to S. S. Harris for his support preparing this manuscript, and we thank B. I. Lee for help with the figures. We acknowledge the donors of Alzheimer’s Disease Research (ADR), a program of BrightFocus Foundation, for the generous support of this research (grant number: A2019112S). M.A.B. is further supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the Medical Research Council, Alzheimer’s Society and Alzheimer Research UK and by a UKRI Future Leaders Fellowship (grant number: MR/S017003/1). B.T.H. is supported by the Massachusetts Alzheimer’s Disease Research Center (P30AG062421), the JPB foundation, the National Institutes of Health (R01AG058674) and the Tau Consortium.

Author information

Authors and Affiliations

  1. UK Dementia Research Institute at UCL, University College London, London, UK

    Marc Aurel Busche

  2. MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, USA

    Bradley T. Hyman

Authors
  1. Marc Aurel Busche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bradley T. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.A.B. and B.T.H. conceived the original idea and wrote the paper.

Corresponding author

Correspondence to Marc Aurel Busche.

Ethics declarations

Competing interests

The authors declare no competing interests related to this project.

Additional information

Peer review information Nature Neuroscience thanks Tong Li and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Busche, M.A., Hyman, B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat Neurosci 23, 1183–1193 (2020). https://doi.org/10.1038/s41593-020-0687-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-020-0687-6

This article is cited by

Search

Advanced 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