Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life


Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer‘s disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer‘s disease—currently defined as Aβ deposition without clinical symptoms—may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Targeting Aβ seeds at the pre-amyloid stage.
Fig. 2: Brain Aβ assemblies recognized by the different antibodies.
Fig. 3: Removal of higher-molecular-weight Aβ assemblies in cmAducanumab-treated mice.
Fig. 4: Pharmacokinetics and target engagement of antibodies at the pre-amyloid stages.
Fig. 5: Targeting pre-amyloid Aβ seeds leads to long-lasting reduction of cerebral β-amyloidosis.
Fig. 6: Targeting pre-amyloid Aβ seeds reduces p-Tau+ neuronal dystrophy and microglial activation.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.


  1. 1.

    Jack, C. R. Jr et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Panza, F., Lozupone, M., Seripa, D. & Imbimbo, B. P. Amyloid-β immunotherapy for Alzheimer disease: is it now a long shot? Ann. Neurol. 85, 303–315 (2019).

    PubMed  Google Scholar 

  4. 4.

    McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Villemagne, V. L., Doré, V., Burnham, S. C., Masters, C. L. & Rowe, C. C. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat. Rev. Neurol. 14, 225–236 (2018).

    CAS  PubMed  Google Scholar 

  6. 6.

    McDade, E. & Bateman, R. J. Stop Alzheimer’s before it starts. Nature 547, 153–155 (2017).

    CAS  PubMed  Google Scholar 

  7. 7.

    Palmqvist, S., Mattsson, N. & Hansson, O. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Thal, D. R. et al. Estimation of amyloid distribution by [18F]flutemetamol PET predicts the neuropathological phase of amyloid β-protein deposition. Acta Neuropathol. 136, 557–567 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Landau, S. M., Horng, A. & Jagust, W. J. Memory decline accompanies subthreshold amyloid accumulation. Neurology 90, e1452–e1460 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    La Joie, R. et al. Multisite study of the relationships between antemortem [11C]PIB-PET centiloid values and postmortem measures of Alzheimer’s disease neuropathology. Alzheimers Dement. 15, 205–216 (2019).

    PubMed  Google Scholar 

  11. 11.

    Ye, L. et al. Aβ seeding potency peaks in the early stages of cerebral β‐amyloidosis. EMBO Rep. 18, 1536–1544 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Aoyagi, A. et al. Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Sci. Transl. Med. 11, eaat8462 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Fuller, J. P., Stavenhagen, J. B. & Teeling, J. L. New roles for Fc receptors in neurodegeneration: the impact on immunotherapy for Alzheimer’s disease. Front. Neurosci. 8, 235 (2014).

  14. 14.

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

    CAS  PubMed  Google Scholar 

  15. 15.

    Eisele, Y. S. et al. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J. Neurosci. 34, 10264–10273 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Güntert, A., Döbeli, H. & Bohrmann, B. High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience 143, 461–475 (2006).

    PubMed  Google Scholar 

  17. 17.

    Frost, J. L. et al. Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am. J. Pathol. 183, 369–381 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Rijal Upadhaya, A. et al. Biochemical stages of amyloid-β peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer’s disease. Brain 137, 887–903 (2014).

    PubMed  Google Scholar 

  19. 19.

    Ye, L. et al. Persistence of Aβ seeds in APP null mouse brain. Nat. Neurosci. 18, 1559–1561 (2015).

    CAS  PubMed  Google Scholar 

  20. 20.

    Arndt, J. W. et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci. Rep. 8, 6412 (2018).

  21. 21.

    Nyström, S. et al. Evidence for age-dependent in vivo conformational rearrangement within Aβ amyloid deposits. ACS Chem. Biol. 8, 1128–1133 (2013).

    PubMed  Google Scholar 

  22. 22.

    Bacioglu, M. et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91, 56–66 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Jarrett, J. T. & Lansbury, P. T. Jr. Seeding ‘one-dimensional crystallization’ of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73, 1055–1058 (1993).

    CAS  PubMed  Google Scholar 

  24. 24.

    Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Katzmarski, N. et al. Aβ oligomers trigger and accelerate Aβ seeding. Brain Pathol. 30, 36–45 (2020).

    CAS  PubMed  Google Scholar 

  27. 27.

    Michno, W. et al. Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1-40 deposition underlies plaque polymorphism in progressing Alzheimer’s disease pathology. J. Biol. Chem. 294, 6719–6732 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Nussbaum, J. M. et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 485, 651–655 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    CAS  PubMed  Google Scholar 

  30. 30.

    Fuller, J. P. et al. Comparing the efficacy and neuroinflammatory potential of three anti-Abeta antibodies. Acta Neuropathol. 130, 699–711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    DeMattos, R. B. et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron 76, 908–920 (2012).

    CAS  PubMed  Google Scholar 

  32. 32.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Pfeifer, M. et al. Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 298, 1379 (2002).

    CAS  PubMed  Google Scholar 

  34. 34.

    Boche, D. et al. Consequence of Aβ immunization on the vasculature of human Alzheimer’s disease brain. Brain 131, 3299–3310 (2008).

    CAS  PubMed  Google Scholar 

  35. 35.

    Sperling, R. A. et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 7, 367–385 (2011).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kollmer, M. et al. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue. Nat. Commun. 10, 4760 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Karlnoski, R. A. et al. Suppression of amyloid deposition leads to long-term reductions in Alzheimer’s pathologies in Tg2576 mice. J. Neurosci. 29, 4964–4971 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Das, P. et al. Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology. Mol. Neurodegener. 7, 39 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Arosio, P., Knowles, T. P. J. & Linse, S. On the lag phase in amyloid fibril formation. Phys. Chem. Chem. Phys. 17, 7606–7618 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    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).

    CAS  PubMed  Google Scholar 

  41. 41.

    Pletnikova, O. et al. Alzheimer lesions in the autopsied brains of people 30 to 50 years of age. Cogn. Behav. Neurol. 28, 144–152 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sperling, R. A., Mormino, E. & Johnson, K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron 84, 608–622 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Westermark, G. T., Fändrich, M., Lundmark, K. & Westermark, P. Noncerebral amyloidoses: aspects on seeding, cross-seeding, and transmission. Cold Spring Harb. Perspect. Med. 8, a024323 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    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).

    PubMed  Google Scholar 

  45. 45.

    Maia, L. F. et al. Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models. EMBO Mol. Med. 7, 895–903 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Maier, F. C. et al. Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion. Nat. Med. 20, 1485–1492 (2014).

    CAS  PubMed  Google Scholar 

  48. 48.

    Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).

    CAS  PubMed  Google Scholar 

  49. 49.

    Bohrmann, B. et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J. Alzheimers Dis. 28, 49–69 (2012).

    CAS  PubMed  Google Scholar 

  50. 50.

    DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 98, 8850–8855 (2001).

    CAS  PubMed  Google Scholar 

  51. 51.

    Adolfsson, O. et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique Aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J. Neurosci. 32, 9677–9689 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Paganetti, P. A., Lis, M., Klafki, H. W. & Staufenbiel, M. Amyloid precursor protein truncated at any of the γ-secretase sites is not cleaved to β-amyloid. J. Neurosci. Res. 46, 283–293 (1996).

    CAS  PubMed  Google Scholar 

  53. 53.

    DeMattos, R. B. et al. Plaque-associated disruption of CSF and plasma amyloid-β (Aβ) equilibrium in a mouse model of Alzheimer’s disease. J. Neurochem. 81, 229–236 (2002).

    CAS  PubMed  Google Scholar 

  54. 54.

    Winkler, D. T. et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci. 21, 1619–1627 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Rasmussen, J. et al. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, 13018–13023 (2017).

    CAS  PubMed  Google Scholar 

  56. 56.

    Schelle, J. et al. Early Aβ reduction prevents progression of cerebral amyloid angiopathy. Ann. Neurol. 86, 561–571 (2019).

    CAS  PubMed  Google Scholar 

  57. 57.

    Bagriantsev, S. N., Kushnirov, V. V. & Liebman, S. W. Analysis of amyloid aggregates using agarose gel electrophoresis. Methods Enzymol. 412, 33–48 (2006).

    CAS  PubMed  Google Scholar 

  58. 58.

    Preische, O. et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat. Med. 25, 277–283 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank G. Salvadori, M. Lambert, L. Häsler, J. Odenthal and all other members of our departments for experimental help. This work was supported by the EC Joint Programme on Neurodegenerative Diseases under the grants JPND-NewTargets and JPND-REfrAME (to M.J.), from the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking (IMPRiND consortium grant no. 116060 to M.J.), the Alexander von Humboldt Foundation (to L.C.W.) and National Institutes of Health grant nos. P50 AG025688 and ORIP/OD P51OD011132 (to L.C.W.).

Author information




R.E.U., J.S., S.K.F., L.Y., U.O., M.S. and M.J. designed and performed the passive immunization and seeding experiments. C.R., J.R., C.B., A.B., F.B., R.A., N.B., S.A.K., U.O., M.S. and M.J. designed and performed the biochemical and histological work. R.E.U., E.M.U.G., A.B. and M.S. designed and performed the pharmacokinetics work. A.S. contributed to data acquisition and data analysis. S.C., F.K., J.B.S., J-U.R., H.C., F.Q., P.H.W. and T.B. contributed the antibodies and provided experimental input. M.S., L.C.W. and M.J. designed the overall study; together with R.E.U., C.R., J.R. and E.M.U.G., they wrote the manuscript. All other coauthors edited the manuscript.

Corresponding author

Correspondence to Mathias Jucker.

Ethics declarations

Competing interests

S.C., F.K. and J.B.S. are current or former employees of Lundbeck. F.Q., P.H.W. and T.B. are current employees and/or shareholders of Biogen. J.-U.R and H.C. are former employees of Probiodrug AG; M.S. is a former employee of Novartis. The other authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks the anonymous reviewers 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.

Extended data

Extended Data Fig. 1 Semi-native agarose gel electrophoresis of synthetic Aβ.

Semi-native agarose gel electrophoresis was performed using monomeric, oligomeric and fibrillar Aβ, in the same fashion as the first steps of the ARPA method, to determine Aβ distribution among fractions. Monomeric Aβ was prepared using Aβ1-40 (Bachem) in DMSO. The oligomeric preparation followed a protocol for Aβ-derived diffusible ligands (Ryan, D. A., Narrow, W. C., Federoff, H. J. & Bowers, W. J. An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. J. Neurosci. Methods 190, 171–179, 2010) using Aβ1-42, and fibrils were prepared by incubating 100 μM Aβ1-42 at 37 °C for 24 hours. Agarose lanes were cut as described in Fig. 2a and the Methods section; agarose gel pieces were melted followed by denaturing immunoblotting and then probed for Aβ with antibody 6E10. Chemiluminescent signal was captured with Amersham Hyperfilm ECL (in contrast to the chemiluminescent imager used for quantitative analysis in Fig. 2). See also Methods for details. Note that (presumed) monomeric Aβ runs in fractions 6 and 7, whereas oligomeric Aβ species are additionally seen in fractions 4 and 5, and Aβ fibrils are in fractions 1 to 3. This experiment was done independently twice with similar results. Source data

Extended Data Fig. 2 Aβ assemblies from AD brain, ARPA and seeding activity.

a, PBS-homogenates from the frontal cortex of three AD subjects (Braak stage VI) were pooled to get a representative sample. ARPA (see Fig. 2 for a description) is shown for the various antibodies. Immunoblots were probed with Aβ-antibody 6E10. The experiment was repeated 3 times with similar results. b, AD brain fractions (F)1-7 and their dilutions were injected into the hippocampus of young, pre-depositing 2- to 3-month-old male APP23 host mice. Brains were immunohistochemically analyzed for Aβ deposition 8 months later. c, Results for F2 and F5 (both undiluted) is shown and reveal a high seeding activity for F2 and no seeding for F5. Scale bar: 500 μm. d, Number of mice with induced Aβ deposition/total mice per group at each dilution from the various fractions (initially all groups had 6-7 mice, of which 4 treated with the undiluted F2 fraction died). e, SD50 for the different fractions was defined as the negative log10 of the brain extract dilution at which 50% of the host mice showed induced Aβ deposition (see Methods). The specific seeding activity (SD50/total Aβ) for each fraction is shown and indicates a peak for F4. Source data

Extended Data Fig. 3. Semiquantitative comparison of signals obtained by ARPA in young, predepositing APP23 mice.

ARPA was performed in PBS homogenates from young, 6-month-old male APP23 brains as presented in Fig. 2d. For semiquantitative analysis, densitometric values of fractions (F) 6 and 7 obtained from the chemiluminescence imager were normalized to the time of exposure. The signal per second was calculated from the five longest exposure times or the five exposure times before signal saturation and the mean was taken. The obtained signal per second for Ctrl1/2 was considered as background, and therefore subtracted from the values calculated for all other antibodies, which were in total set equal to 100%. Relative values for each fraction were plotted. Beta1 and mC2 show similar signal-to-second values. The highest signal-per-second was obtained from m266, whereas the lowest signals were calculated for cmAdu and mE8 (see insert). All data are represented as means (n = 3 experiments) ± SEMs. For details see Fig. 2d.

Extended Data Fig. 4 Lack of detectable Aβ antibody titers in normal and control antibody-treated APP23 mice.

Plasma was taken for analysis from randomly selected 6-month-old male APP23 tg mice, either non-treated (tg, n = 5) or treated for 5 consecutive days with Ctrl1 or Ctrl2 antibody and analyzed 6 weeks later (n = 5/group; same mice as presented in Fig. 1). As a positive control, plasma from the Beta1- and cmAdu-injected mice one day after the injection were included (n = 5 each) together with a pool of non-tg mice as a further negative control. Two different ELISA setups were used and performed on two consecutive days, one optimized to measure Beta1 titers a, and another one optimized to measure cmAdu titers b–d, (see Methods). Data are represented as group means ± SEMs. Results reveal that the injections of Ctrl antibodies into APP23 tg or non-tg mice did not induce Aβ antibody titers. Further, no detectable titers were found in untreated APP23 tg or non-tg mice.

Supplementary information

Source data

Source Data Fig. 2

Unprocessed western blots.

Source Data Fig. 3

Unprocessed western blots Fig. 3a.

Source Data Extended Data Fig. 1

Unprocessed western blots.

Source Data Extended Data Fig. 2

Unprocessed western blots Fig. 2a.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Uhlmann, R.E., Rother, C., Rasmussen, J. et al. Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life. Nat Neurosci 23, 1580–1588 (2020).

Download citation

Further reading


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