The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
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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Citations
Cites
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LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms
Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H. W., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.07.017 · Cited by 828
Cited by
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Items 401–426 of 426
Zoltowska, K. M., Das, U., Lismont, S., Enzlein, T., Maesako, M., Mei, C. H., Franco, M. L., Moreira, D. G., Karachentsev, D., Becker, A., et al. (2023) · eLife · doi:10.7554/elife.90690.1
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Bridging the Gap—Thermofluidic Designs for Precision Bioelectronics
Ma, J., Majmudar, A., & Tian, B. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302431
Negative Regulation of Cathepsins by β-Amyloid
Lundin, B., Comby, A.-C., Berezovska, O., & Maesako, M. (2024) · eNeuro · doi:10.1523/eneuro.0258-23.2023 · Cited by 2
“In the experiment, 1 µM A β 38, A β 40, A β 42, or A β 43 was incubated with recombinant CTSB and AFC-conjugated CTSB substrate as the concentration of A β is estimated to be at micrometer range in the endo-lysosomal compartments (Hu et al., 2009; Schützmann et al., 2021).”
MethodAn overview on Alzheimer’s disease, diagnosis and treatment approach
Nivetha, S. R., Shivani, K., Vigneshwaran, R., Prasanna, G. L., & Veeramani, M. (2023) · International Journal of Allied Medical Sciences and Clinical Research · doi:10.61096/ijamscr.v11.iss4.2023.379-391 · Cited by 1
Zoltowska, K. M., Das, U., Lismont, S., Enzlein, T., Maesako, M., Houser, M. C., Franco, M. L., Özcan, B., Moreira, D. G., Karachentsev, D., et al. (2024) · eLife · doi:10.7554/elife.90690.2
Farnum, Z., Mani, R., Bindoff, A. D., Wilson, R., Fiotakis, A., Stephens, J., Cho, H., Mackay‐Sim, A., & Sinclair, D. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16263
“…immunofluorescent staining of A β 40 and a small amount of immunofluorescent staining of A β 42 (see Figure S2), consistent with uniform distribution of predominantly A β monomers and/or small oligomers throughout the cul - ture media, and to some extent, within cells (as per (Hu et al., 2009 )).”
ApoE Receptors, Molecular Processes, and Cellular Signaling Pathways
Jaeschke, A., & Hui, D. Y. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_6-1
Walker, W. P., Ratz-Mitchem, M. L., Wagner, K., & Gunn, T. M. (2025) · Biomolecules · doi:10.3390/biom15060786
“…β ) and CTFs is believed to occur, at least in part, in early endosomes [35–38], and the acidic environment of late endosomes or lysosomes would promote the self-assembly of A β peptides into fibrils that seed plaque formation when released from the cell, perhaps via exosomes or other EVs [39–41].”
Özkurt, Ç., Köse, S., Karasu, Ç., Kortholt, A., & Kelicen‐Uğur, P. (2025) · Research Square · doi:10.21203/rs.3.rs-7094261/v1
Proteinvermittelte Kupfer‐Redoxregulation: Rolle von Disulfidbrücken und allosterischer Modulation
Sternke‐Hoffmann, R., Liu, C., Wang, X., Pupart, H., Sun, X., Dreiser, J. G., Palumaa, P., Liao, Q., Krack, M., & Luo, J. (2026) · Angewandte Chemie · doi:10.1002/ange.202519673
Chaperone proteins protect against desmin fragment amyloid aggregation
Mulhearn, E. M., & Alperstein, A. M. (2026) · Biophysical Journal · doi:10.1016/j.bpj.2026.03.038
“Seeding experiments are common in the amyloid field because these experiments mimic conditions that allow aggregates to spread through formerly healthy tissue (51).”
Binding and internalization of exogenous protein assemblies by mammalian cells
Ruiz-Arlandis, G. (2015) · theses.fr (ABES) · doi:10.70675/437e0532ze4e1z4966z80e5z340b6fd3c49d
Exosomes in Amyloid Propagation—Roles in Neurodegeneration
Mishra, R., & Upadhyay, A. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05913-w
Özkurt, Ç., Köse, S., Karasu, Ç., Kortholt, A., & Kelicen‐Uğur, P. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04792-w
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Quijano-Guerrero, D. P., Estrada-Rodríguez, A. E., Caballero-Rodríguez, M., de León-Rivera, D. L., Rodrı́guez-Padilla, C., Valdés, V. J., Caballero-Hernández, D. E., Vidaltamayo, R., Martínez‐Torres, A. C., & Zomosa‐Signoret, V. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1843210
“Some studies have found that treating cells with A β 42 activates autophagy by decreasing mTOR signaling and increasing LC3 levels, a human homologue of ATG8 (Chan et al., 2018; de la Cueva et al., 2022; Hu et al., 2009; Pomilio et al., 2020).”
DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer’s disease
Wong, H. Y., Jin, C., Yuen, S. L., Yang, X., Gill, S. S., Xu, J., Lai, K. P. E., Fu, W., Gao, W., Wang, X., et al. (2026) · EMBO Molecular Medicine · doi:10.1038/s44321-026-00488-4
“…species and neighboring neurons, microglia, and astrocytes play a pivotal role in AD pathogenesis, creating unique micro-environments that affect synaptic integrity, in fl ammatory signaling, and disease progression (Baik et al, 2016; Holtzman et al, 2000; Hu et al, 2009; Lemke and Huang, 2022).”
Revisiting the role of amyloid-β: A molecular and immunological perspective
Slama, P. S. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261484863
“233,234 Even in experiments using A β 42 , different molecular behaviors can be observed depending on the process used to generate the polypeptide or oligomers and on the development stage of the neurons used.”
Aggregated amyloid-β(1-42) is internalized more efficiently than monomers by HEK293T cells
Pereira, C. S., Abid, H., Adair, C., Domalewski, R. J., Jabr, L., & Nichols, M. R. (2026) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2026.141178
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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