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Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity
Open accessAbstract
The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.
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“Although amyloid beta plaques are extracellular, mounting evidence suggests that aggregation also begins within neurons, where uptake and subsequent degradation within lysosomes has been dysregulated leading to intraneuronal accumulation leading to aggregation [14–20].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [18]
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“Endosomal Aβ42 labeling by immuno-EM has since been confirmed by other groups [49, 95, 143].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [49]
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APP processing in Alzheimer’s disease.
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“logical effect [155].”
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“In the AD brain and diabetic pancreas, amyloid plaques arise from the aggregation of pre-fibrillar amyloidogenic peptides such as the Aβ(1-42) peptide17, 18, 19 or IAPP20, 21, 22, which oligomerize and give rise to higher order structures, including fibrils.”
BackgroundMultivesicular Body Morphogenesis
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“Accumulation of intraneuronal amyloid-beta (Aβ) in MVBs may be associated with abnormal synaptic morphology in AD (Takahashi et al. 2002), and Aβ in MVBs may assemble into oligomers that initiate pathological changes (Friedrich et al. 2010, Takahashi et al. 2004).”
BackgroundWu, J. W., Herman, M., Liu, L., Simoes, S., Acker, C. M., Figueroa, H., Steinberg, J. I., Margittai, M., Kayed, R., Zurzolo, C., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.394528 · Cited by 537
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“studies have indicated the presence of Aβ42 in endosomes and late endosomal multivesicular bodies in other models [30-32] and in cathepsin-D-positive puncta of 5XFAD mice [25].”
Result
Metadata
- Authors
- Friedrich, R. P., Tepper, K., Rönicke, R., Soom, M., Westermann, M., Reymann, K., Kaether, C., & Fändrich, M.
- Affiliations
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Leibniz Institute for Neurobiology (DE)
- Friedrich Schiller University Jena (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-01-19
- Volume
- 107
- Issue
- 5
- Pages
- 1942-1947
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2836607
- OpenAlex
- W2036172794
- Cited by
- 303
- References
- 63
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 20 · 2023: 20 · 2022: 13 · 2021: 21 · 2020: 23 · 2019: 11 · 2018: 30 · 2017: 28 · 2016: 15 · 2015: 18 · 2014: 8 · 2013: 24 · 2012: 13
- FWCI
- 15.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid plaque formation, amyloid-beta, Alzheimer's disease, multivesicular bodies, endocytosis, phagocytosis, cell death, amyloid-beta oligomers
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Chlorocebus aethiops, Freeze Fracturing, Humans, Intracellular Fluid, Microscopy, Electron, Scanning, Peptide Fragments, Amyloid beta-Peptides, Microscopy, Video, COS Cells, Mice, Plaque, Amyloid
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