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Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates


Previous reports showed that brain Aβ amyloidosis can be induced in animal models by exogenous administration of pre-formed aggregates. To date, only intra-peritoneal and intra-venous administrations are described as effective means to peripherally accelerate brain Aβ amyloidosis by seeding. Here, we show that cerebral accumulation of Aβ can be accelerated after exposing mouse models of Alzheimer’s disease (AD) to Aβ seeds by different peripheral routes of administration, including intra-peritoneal and intra-muscular. Interestingly, animals receiving drops of brain homogenate laden with Aβ seeds in the eyes were efficiently induced. On the contrary, oral administration of large quantities of brain extracts from aged transgenic mice and AD patients did not have any effect in brain pathology. Importantly, pathological induction by peripheral administration of Aβ seeds generated a large proportion of aggregates in blood vessels, suggesting vascular transport. This information highlights the role of peripheral tissues and body fluids in AD-related pathological changes.

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Fig. 1: Tg2576 mice challenged with Aβ seeds by different routes developed accelerated brain amyloidosis.
Fig. 2: Evaluation of insoluble Aβ42 levels in Tg2576 mice receiving biologically active seeds by peripheral routes.
Fig. 3: Comparison of Aβ burden between seeded and untreated Tg2576 sacrificed at different time points.
Fig. 4: Seeded Aβ deposits in the brain of Tg2576 mice are highly associated with blood vessels.
Fig. 5: Regional profile of Aβ deposition in exogenously induced mice compared with untreated aged animals.
Fig. 6: Morphological and staining differences in Aβ deposits induced by different routes of administration.


  1. Mrcpsych B, Jones E, Ballard C, Gauthier S, Corbett A, Brayne C, et al. Alzheimer’s disease. Lancet. 2011;377:1019–31.

    Article  Google Scholar 

  2. Querfurth HW, LaFerla FM. Alzheimer’s Disease. N. Engl J Med. 2010;362:329–44.

    Article  CAS  Google Scholar 

  3. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:49–60.

    Article  CAS  Google Scholar 

  4. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s Disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction. Neuron. 2003.

  5. Götz J, Chen F, Van Dorpe J, Nitsch RM Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science. 2001.

  6. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001.

  7. He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2018.

  8. Bucciantini M, Calloni G, Chiti F, Formigli L, Nosi D, Dobson CM, et al. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem. 2004.

  9. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem. 2005;280:17294–17300.

    Article  CAS  Google Scholar 

  10. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. NatMed. 2008;14:837–42.

    CAS  Google Scholar 

  11. Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B, et al. Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002.

  12. Katzmarski N, Ziegler-Waldkirch S, Scheffler N, Witt C, Abou-Ajram C, Nuscher B, et al. Aβ oligomers trigger and accelerate Aβ seeding. Brain Pathol. 2020.

  13. Ziegler‐Waldkirch S, d′Errico P, Sauer J, Erny D, Savanthrapadian S, Loreth D, et al. Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer’s disease. EMBO J. 2018.

  14. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6.

    Article  CAS  Google Scholar 

  15. Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, et al. Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science. 1992;258:668–71.

    Article  CAS  Google Scholar 

  16. Morales R, Callegari K, Soto C. Prion-like features of misfolded Aβ and tau aggregates. Virus Res. 2015;207:106–12.

    Article  CAS  Google Scholar 

  17. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45–51.

    Article  CAS  Google Scholar 

  18. Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, et al. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β-amyloid precursor protein-transgenic mice. J Neurosci. 2000;20:3606–11.

    Article  CAS  Google Scholar 

  19. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006;313:1781–4.

    Article  CAS  Google Scholar 

  20. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Induction of beta (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol Neurobiol. 1994;8:25–39.

    Article  CAS  Google Scholar 

  21. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C. De novo induction of amyloid-β deposition in vivo. Mol Psychiatry. 2012;17:1347–53.

    Article  CAS  Google Scholar 

  22. Rosen RF, Fritz JJ, Dooyema J, Cintron AF, Hamaguchi T, Lah JJ, et al. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J Neurochem. 2012;120:660–6.

    Article  CAS  Google Scholar 

  23. Morales R, Bravo-Alegria J, Duran-Aniotz C, Soto C. Titration of biologically active amyloid-β seeds in a transgenic mouse model of Alzheimer’s disease. Sci Rep. 2015;5:9349.

    Article  CAS  Google Scholar 

  24. Watts JC, Condello C, Stöhr J, Oehler A, Lee J, DeArmond SJ, et al. Serial propagation of distinct strains of Aβ prions from Alzheimer’s disease patients. Proc Natl Acad Sci USA. 2014;111:10323–8.

    Article  CAS  Google Scholar 

  25. Stöhr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M, et al. Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci USA. 2014;111:10329–34.

    Article  Google Scholar 

  26. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int J Exp Pathol. 1993;74:441–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gary C, Lam S, Hérard AS, Koch JE, Petit F, Gipchtein P, et al. Encephalopathy induced by Alzheimer brain inoculation in a non-human primate. Acta Neuropathol Commun. 2019.

  28. Ye L, Hamaguchi T, Fritschi SK, Eisele YS, Obermuller U, Jucker M, et al. Progression of seed-induced abeta deposition within the limbic connectome. Brain Pathol. 2015;25:743–52.

  29. Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010;330:980–2.

    Article  CAS  Google Scholar 

  30. Fraser H, Dickinson AG. Studies of the lymphoreticular system in the pathogenesis of scrapie: the role of spleen and thymus. J Comp Pathol. 1978;88:563–73.

    Article  CAS  Google Scholar 

  31. Bartz JC, Dejoia C, Tucker T, Kincaid AE, Bessen RA. Extraneural prion neuroinvasion without lymphoreticular system infection. J Virol. 2005;79:11858–63.

    Article  CAS  Google Scholar 

  32. Kincaid AE, Bartz JC. The nasal cavity is a route for prion infection in hamsters. J Virol. 2007;81:4482–91.

    Article  CAS  Google Scholar 

  33. Eisele YS, Fritschi SK, Hamaguchi T, Obermuller U, Fuger P, Skodras A, et al. Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis. JNeurosci. 2014;34:10264–73.

    Article  Google Scholar 

  34. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, et al. Induction of cerebral β-amyloidosis: intracerebral versus systemic Aβ inoculation. Proc Natl Acad Sci USA. 2009.

  35. Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: patterns of agent replication in different parts of the CNS following intraperitoneal infection. J R Soc Med. 1982;75:618–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bartz JC, Kincaid AE, Bessen RA. Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol. 2002;76:5759–68.

    Article  CAS  Google Scholar 

  37. Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. 2004;363:417–21.

    Article  CAS  Google Scholar 

  38. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102.

  39. Morales Rodrigo, Duran-Aniotz Claudia, Bravo-Alegria Javiera, Estrada LisbellD, Shahnawaz Mohammad, Hu Ping-Ping, et al. AU& CS. Infusion of blood from mice displaying cerebral amyloidosis accelerates amyloid pathology in animal models of Alzheimer’s disease. Acta Neuropathol Commun. 2020;8:213.

    Article  CAS  Google Scholar 

  40. Kawarabayashi T, Younkin L, Saido T, Shoji M, Ashe K, Younkin S. Age-dependent changes in brain, CSF, and plasma amyloid Î2 protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci. 2001.

  41. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Fedynyshyn J, Soto C. Aggregate-depleted brain fails to induce Aβ deposition in a mouse model of Alzheimer’s disease. PLoS One. 2014;9:e89014.

    Article  Google Scholar 

  42. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Soto C. Brains from non-Alzheimer’s individuals containing amyloid deposits accelerate Abeta deposition in vivo. Acta NeuropatholCommun. 2013;1:76.

    Article  Google Scholar 

  43. Wilcock DM, Gordon MN, Morgan D. Quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with Congo red histochemical stain. Nat Protoc. 2006.

  44. Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: effect of route of inoculation on infectivity titres and dose-response curves. J Comp Pathol. 1978.

  45. Urayama A, Morales R, Niehoff ML, Banks WA, Soto C. Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake. FASEB J. 2011;25:2792–803.

    Article  CAS  Google Scholar 

  46. Fraser H, Dickinson AG. Pathogenesis of scrapie in the mouse: the role of the spleen. Nature. 1970;226:462–3.

    Article  CAS  Google Scholar 

  47. Kelényi G Thioflavin S. fluorescent and congo red anisotropic stainings in the histologic demonstration of amyloid. Acta Neuropathol. 1967.

  48. Soto C. Transmissible proteins: expanding the prion heresy. Cell. 2012;149:968–77.

    Article  CAS  Google Scholar 

  49. Zhang B, Une Y, Fu X, Yam J, Ge F, Yao J, et al. Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci USA. 2008.

  50. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14:504–6.

    Article  CAS  Google Scholar 

  51. Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H. Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly 2016.

  52. Kovacs GG, Lutz MI, Ricken G, Ströbel T, Höftberger R, Preusser M, et al. Dura mater is a potential source of Aβ seeds. Acta Neuropathol. 2016;131:911–23.

    Article  CAS  Google Scholar 

  53. Jaunmuktane Z, Mead S, Ellis M, Wadsworth JDF, Nicoll AJ, Kenny J, et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 2015;525:247–50.

    Article  CAS  Google Scholar 

  54. Ritchie DL, Adlard P, Peden AH, Lowrie S, Le Grice M, Burns K, et al. Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 2017;134:221–40.

    Article  CAS  Google Scholar 

  55. Soto C, Estrada L, Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci. 2006;31:150–5.

    Article  CAS  Google Scholar 

  56. Walker L, Levine H, Jucker M. Koch’s postulates and infectious proteins. Acta Neuropathol. 2006;112:1–4.

    Article  CAS  Google Scholar 

  57. DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A antibody alters CNS and plasma A clearance and decreases brain A burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci. 2001.

  58. Mackic JB, Bading J, Ghiso J, Walker L, Wisniewski T, Frangione B, et al. Circulating amyloid-β peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer’s disease lesions. Vascul Pharmacol. 2002.

  59. Ghilardi JR, Catton M, Stimson ER, Rogers S, Walker LC, Maggio JE, et al. Intra-arterial infusion of [125I]A beta 1-40 labels amyloid deposits in the aged primate brain in vivo. Neuroreport. 1996;7:2607–11.

  60. Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M. The presence of Abeta seeds, and not age per se, is critical to the initiation of Abeta deposition in the brain. Acta Neuropathol. 2012;123:31–37.

    Article  CAS  Google Scholar 

  61. Ye L, Fritschi SK, Schelle J, Obermüller U, Degenhardt K, Kaeser SA, et al. Persistence of Aβ seeds in APP null mouse brain. Nat Neurosci. 2015;18:1559–61.

  62. Maclean CJ, Baker HF, Ridley RM, Mori H. Naturally occurring and experimentally induced β-amyloid deposits in the brains of marmosets (Callithrix jacchus). J Neural Transm. 2000.

  63. Shearin H, Bessen RA. Axonal and transynaptic spread of prions. J Virol. 2014;88:8640–55.

    Article  Google Scholar 

  64. Thal DR, Walter J, Saido TC, Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol. 2015;129:167–82.

  65. Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, Ghosh JG, et al. Alzheimer’s disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One. 2010.

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The authors would like to thank Mrs. Andrea Flores-Ramirez for animal care and genotyping. This work was supported by grants from the NIH (RF1 AG061069 to CS and RF1 AG059321 to CS and RM), the Alzheimer’s Association (MNIRGD-12-243075 and NIRGD-15-363554 to RM, NIRP-12-257323 to IM-G and AARG-591107 to CDA), grants from ANID (ANID/FONDEF ID20I10152 and ANID/FONDECYT 1210622) to CDA, a grant from The Mitchell Foundation (to CS), and a Ramon y Cajal Program (RYC-2017-21879) to IM-G. We also acknowledge the use of tissues procured by the National Disease Research Interchange (NDRI) with support from NIH grant U42OD11158.

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RM and CS designed the experiments. RM, JB-A, IM-G, CD-A, NG and GEIII performed the experimental work. RM, JB-A, IM-G and CS analyzed the data. RM wrote the manuscript. All authors reviewed and approved the final version of this article.

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Correspondence to Rodrigo Morales or Claudio Soto.

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Morales, R., Bravo-Alegria, J., Moreno-Gonzalez, I. et al. Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates. Mol Psychiatry 26, 5690–5701 (2021).

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