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Soluble Aβ Seeds Are Potent Inducers of Cerebral β-Amyloid Deposition
Open accessAbstract
Cerebral β-amyloidosis and associated pathologies can be exogenously induced by the intracerebral injection of small amounts of pathogenic Aβ-containing brain extract into young β-amyloid precursor protein (APP) transgenic mice. The probable β-amyloid-inducing factor in the brain extract has been identified as a species of aggregated Aβ that is generated in its most effective conformation or composition in vivo. Here we report that Aβ in the brain extract is more proteinase K (PK) resistant than is synthetic fibrillar Aβ, and that this PK-resistant fraction of the brain extract retains the capacity to induce β-amyloid deposition upon intracerebral injection in young, pre-depositing APP23 transgenic mice. After ultracentrifugation of the brain extract, <0.05% of the Aβ remained in the supernatant fraction, and these soluble Aβ species were largely PK sensitive. However, upon intracerebral injection, this soluble fraction accounted for up to 30% of the β-amyloid induction observed with the unfractionated extract. Fragmentation of the Aβ seeds by extended sonication increased the seeding capacity of the brain extract. In summary, these results suggest that multiple Aβ assemblies, with various PK sensitivities, are capable of inducing β-amyloid aggregation in vivo. The finding that small and soluble Aβ seeds are potent inducers of cerebral β-amyloidosis raises the possibility that such seeds may mediate the spread of β-amyloidosis in the brain. If they can be identified in vivo, soluble Aβ seeds in bodily fluids also could serve as early biomarkers for cerebral β-amyloidogenesis and eventually Alzheimer's disease.
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“Our recent finding that the most effective Aβ seeds are small and soluble”
From Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders (2011) · cites this paper as [54]
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“Because the most potent Aβ seeds, like prions97, appear to be relatively small54, soluble Aβ seeds could serve as informative biomarkers in bodily fluids.”
From Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders (2011) · cites this paper as [54]
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Additional file 1 of Remodeling Alzheimer-amyloidosis models by seeding
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Additional file 1 of Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice
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Metadata
- Authors
- Langer, F., Eisele, Y. S., Fritschi, S. K., Staufenbiel, M., Walker, L. C., & Jucker, M.
- Affiliations
- Hertie Institute for Clinical Brain Research (DE)
- German Center for Neurodegenerative Diseases (DE)
- Novartis (Switzerland) (CH)
- Emory University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-10-12
- Volume
- 31
- Issue
- 41
- Pages
- 14488-14495
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3229270
- OpenAlex
- W1991462232
- Cited by
- 237
- References
- 49
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 29 · 2020: 12 · 2019: 15 · 2018: 19 · 2017: 16 · 2016: 24 · 2015: 20 · 2014: 29 · 2013: 19 · 2012: 14
- FWCI
- 14.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung (01GI0705)
- National Institutes of Health (RR‐00165)
- National Center for Research Resources (P51RR000165)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- amyloid-beta aggregation, proteinase K resistance, APP23 transgenic mice, intracerebral injection, sonication, Alzheimer's disease, biomarkers
- MeSH terms
- Animals, Brain, Cerebral Cortex, Enzyme-Linked Immunosorbent Assay, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, Sonication, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Endopeptidase K, Mice
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