Abstract
Alzheimer's disease (AD), the most common type of senile dementia, is associated to the build-up of misfolded amyloid-β (Aβ) in the brain. Although compelling evidences indicate that the misfolding and oligomerization of Aβ is the triggering event in AD, the mechanisms responsible for the initiation of Aβ accumulation are unknown. In this study, we show that Aβ deposition can be induced by injection of AD brain extracts into animals, which, without exposure to this material, will never develop these alterations. The accumulation of Aβ deposits increased progressively with the time after inoculation, and the Aβ lesions were observed in brain areas far from the injection site. Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lee VM, Goedert M, Trojanowski JQ . Neurodegenerative tauopathies. Annu Rev Neurosci 2001; 24: 1121–1159.
Hardy J, Selkoe DJ . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–356.
Selkoe DJ . Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann NY Acad Sci 2000; 924: 17–25.
Soto C . Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 2003; 4: 49–60.
Aguzzi A, Calella AM . Prions: protein aggregation and infectious diseases. Physiol Rev 2009; 89: 1105–1152.
Soto C . Prion hypothesis: the end of the controversy? Trends Biochem Sci 2011; 36: 151–158.
Lansbury Jr PT . Structural neurology: are seeds at the root of neuronal degeneration? Neuron 1997; 19: 1151–1154.
Soto C, Estrada L, Castilla J . Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci 2006; 31: 150–155.
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: 1781–1784.
Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX et al. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci USA 2009; 106: 12926–12931.
Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 2010; 330: 980–982.
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G et al. High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050–4058.
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274: 99–102.
Kelenyi G . Thioflavin S fluorescent and Congo red anisotropic stainings in the histologic demonstration of amyloid. Acta Neuropathol (Berl) 1967; 7: 336–348.
Tagliavini F, Giaccone G, Frangione B, Bugiani O . Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals. Neurosci Lett 1988; 93: 191–196.
Walker LC, Levine III H, Mattson MP, Jucker M . Inducible proteopathies. Trends Neurosci 2006; 29: 438–443.
Aguzzi A . Cell biology: beyond the prion principle. Nature 2009; 459: 924–925.
Westermark GT, Westermark P . Prion-like aggregates: infectious agents in human disease. Trends Mol Med 2010; 16: 501–507.
Brundin P, Melki R, Kopito R . Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 2010; 11: 301–307.
Frost B, Diamond MI . Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 2010; 11: 155–159.
Collinge J, Whitfield J, McKintosh E, Beck J, Mead S, Thomas DJ et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet 2006; 367: 2068–2074.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009; 11: 909–913.
Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR . Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol 2009; 11: 219–225.
Frost B, Jacks RL, Diamond MI . Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009; 284: 12845–12852.
Acknowledgements
We would like to thank Maria-Jose Liberona for critical review of the manuscript. This work was supported by a grant from the Mitchell Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
Morales, R., Duran-Aniotz, C., Castilla, J. et al. De novo induction of amyloid-β deposition in vivo. Mol Psychiatry 17, 1347–1353 (2012). https://doi.org/10.1038/mp.2011.120
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2011.120
Keywords
This article is cited by
-
Detection of plasma Aβ seeding activity by a newly developed analyzer for diagnosis of Alzheimer’s disease
Alzheimer's Research & Therapy (2022)
-
Remodeling Alzheimer-amyloidosis models by seeding
Molecular Neurodegeneration (2021)
-
Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice
Acta Neuropathologica Communications (2021)
-
Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
Scientific Reports (2021)
-
Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates
Molecular Psychiatry (2021)