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Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide
Open accessAbstract
One of the neuropathological hallmarks of Alzheimer's disease (AD) is the amyloid plaque, primarily composed of aggregated amyloid-beta (Aβ) peptide. In vitro, Aβ 1–42 , the major alloform of Aβ found in plaques, self-assembles into fibrils at micromolar concentrations and acidic pH. Such conditions do not exist in the extracellular fluid of the brain where the pH is neutral and Aβ concentrations are in the nanomolar range. Here, we show that extracellular soluble Aβ (sAβ) at concentrations as low as 1 nM was taken up by murine cortical neurons and neuroblastoma (SHSY5Y) cells but not by human embryonic kidney (HEK293) cells. Following uptake, Aβ accumulated in Lysotracker-positive acidic vesicles (likely late endosomes or lysosomes) where effective concentrations (>2.5 μM) were greater than two orders of magnitude higher than that in the extracellular fluid (25 nM), as quantified by fluorescence intensity using laser scanning confocal microscopy. Furthermore, SHSY5Y cells incubated with 1 μM Aβ 1–42 for several days demonstrated a time-dependent increase in intracellular high molecular weight (HMW) (>200 kDa) aggregates, which were absent in cells grown in the presence of Aβ 1–40 . Homogenates from these Aβ 1–42 -loaded cells were capable of seeding amyloid fibril growth. These results demonstrate that Aβ can be taken up by certain cells at low physiologically relevant concentrations of extracellular Aβ, and then concentrated into endosomes/lysosomes. At high concentrations, vesicular Aβ aggregates to form HMW species which are capable of seeding amyloid fibril growth. We speculate that extrusion of these aggregates may seed extracellular amyloid plaque formation during AD pathogenesis.
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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 [19]
Experimental — accuracy not yet measuredIn the citing paper
“In contrast to the extracellular space, microglial lysosomes provide a suitable environment to facilitate Aβ aggregation, potentially contributing to the onset of plaque pathology15.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [15]
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Yeast as a Model for Studying Aβ Aggregation, Toxicity and Clearance
Bharadwaj, P. (2011) · Australasian Journal of Paramedicine · Cited by 1
A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegenerationPreprint
Ubina, T., Magallanes, M., Srivastava, S., Warden, C., Yee, J., & Salvaterra, P. M. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/419978 · Cited by 1
Wang, Z., Sharda, N., Omtri, R. S., Li, L., & Kandimalla, K. K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.17.516996 · Cited by 1
Amyloid Degradation Toxicity Hypothesis: Integrative Theory of Alzheimer’s DiseasePreprint
Zaretsky, D. V., & Zaretskaia, M. V. (2023) · Preprints.org · doi:10.20944/preprints202306.0807.v2
Modulating Amyloid Beta Clearance by Altering Cellular and Whole Brain Apolipoprotein E Metabolism
Basak, J. M. (2014) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7dz06bk
“As suggested by one study, intraneuronal Aβ accumulation could play a role in promoting AD pathogenesis through the seeding of amyloid formation (Hu et al., 2009).”
Experimental Inhibition of Peptide Fibrillogenesis by Synthetic Peptides, Carbohydrates and Drugs
Srinivasan, A. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-5416-4_12
Simon, D. (2011) · SZTE Repository of Dissertations (University of Szeged) · doi:10.14232/phd.1292
Alzheimer disease: Studies on Aand -secretase in human brain
Welander, H. (2009)
Tam, J. H. K. (2015) · Scholarship@Western (Western University)
Amyloid State of Proteins in Human Disease
Huang, L., & Huang, K. (2015) · Encyclopedia of Life Sciences · doi:10.1002/9780470015902.a0024459
Consequences of Intracellular Amyloid in Vascular System
D’Andrea, M. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-804256-4.00008-5
Characterizing the effect of transthyretin amyloid on the heart
Koch, C. M. (2015) · OpenBU (Boston University)
Alzheimer’s Disease Therapeutics Targeting Apolipoprotein E
Liao, F., & Holtzman, D. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00010-1
In Vitro and In Vivo Studies on Antibodies - N-terminally Truncated Abeta in the 5XFAD Mouse Model
Richard, B. C. (2015) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-5098
Borgers, H. (2017) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-6363
Theoretical Calculation for Removing Tau Protein in Alzheimer Disease
Behrouz, A. H., Zareyi, H., Zhour, K., Tashakori, S., & Vaezzadeh, M. (2018) · Nano Research & Applications · doi:10.21767/2471-9838.100035
Han, J., Nam, E., Yoon, J., Qian, T., Li, Y., Lee, S., & Lim, M. H. (2021) · ChemRxiv · doi:10.26434/chemrxiv.14736882.v1
GM1 mediates the formation and maintenance of cytotoxic Aβ oligomersPreprint
Zhang, D. Y., Wang, J., Fleeman, R. M., Kuhn, M. K., Swulius, M. T., Proctor, E. A., & Dokholyan, N. V. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.22.453392
“The concentration of Aβ is important to the formation of oligomers (Hu et al., 2009; Thal et al., 2015).”
BackgroundAβ-Induced Alterations in Membrane Lipids Occur before Synaptic Loss Appears
Bulck, M. V., Brandt, N., Claus, R. A., Gräler, M. H., & Bräuer, A. U. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042300
Foley, A. R., & Raskatov, J. A. (2022) · ChemBioChem · doi:10.1002/cbic.202200146
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Han, J., Nam, E., Yoon, J., Qian, T., Li, Y., Lee, S., & Lim, M. H. (2021) · ChemRxiv · doi:10.26434/chemrxiv.14736882
Adipokines and Alzheimer's Disease
Sortino, M. A., Merlo, S., & Spampinato, S. F. (2011) · Royal Society of Chemistry eBooks · doi:10.1039/9781849733434-00130
Ogi, S., Takamatsu, A., Matsumoto, K., Hasegawa, S., & Yamaguchi, S. (2023) · Angewandte Chemie · doi:10.1002/ange.202306428
Metadata
- Authors
- Hu, X., Crick, S. L., Bu, G., Frieden, C., Pappu, R. V., & Lee, J.-M.
- Affiliations
- Washington University in St. Louis (US)
- Department of Biomedical Engineering and Center for Computational Biology, and
- Department of Pediatrics, Cell Biology and Physiology, and
- Hope Center for Neurological Disorders (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12
- Volume
- 106
- Issue
- 48
- Pages
- 20324-20329
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2787156
- OpenAlex
- W1968721593
- Cited by
- 426
- References
- 47
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 22 · 2023: 36 · 2022: 30 · 2021: 20 · 2020: 22 · 2019: 26 · 2018: 28 · 2017: 36 · 2016: 24 · 2015: 17 · 2014: 30 · 2013: 23 · 2012: 31
- FWCI
- 15.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Institute on Aging (P01AG030128, R01AG027924)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK13332, R01DK013332)
- National Institute of Neurological Disorders and Stroke (P01 NS32636, R01NS48283, R01 NS67905, R01NS067905, R01NS056114, R01NS048283, P01NS032636)
- 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-beta, amyloid-beta 42, Aβ40, Alzheimer's disease, amyloid plaques, lysosomes, late endosomes, cellular uptake, neuroblastoma cells, cortical neurons, amyloid plaque formation
- MeSH terms
- Alzheimer Disease, Animals, Fluorescence, Humans, Neurons, Thiazoles, Immunoblotting, Amyloid beta-Peptides, Microscopy, Confocal, Cytoplasmic Vesicles, Cell Line, Tumor, Mice, Benzothiazoles, Plaque, Amyloid
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