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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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“However, in the vicinity of synaptic membrane Aβ42 concentration may be substantially higher as firstly it is released from the membrane by cleavage of the transmembrane amyloid precursor protein (APP) abundant in synaptic membrane [49] and, secondly, it can be released from intracellular vesicles, where Aβ reaches mi…”
BackgroundOu-Yang, M.-H., Xu, F., Liao, M.-C., Davis, J., Robinson, J. K., & Nostrand, W. E. V. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.006 · Cited by 14
“…intracellular and extracellular Ab pools and that extracellular amyloid deposition can be changed through targeting intracellular Ab (Billings et al., 2005; Hu et al., 2009; Oddo et al., 2004), we did not find differences in the levels of intracellular Ab in the presence of MBP1 (data not shown).”
Park, Y. D., Park, J. H., Hur, M. G., Kim, S. W., Min, J., Park, S., Yoo, Y. J., Yoon, Y., & Yang, S. D. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.04.068 · Cited by 13
Pani, I., Swasthi, H. M., Mukhopadhyay, S., & Pal, S. K. (2018) · The Journal of Physical Chemistry C · doi:10.1021/acs.jpcc.8b10863 · Cited by 13
Cruceta, L., Sun, Y. P., Kenyaga, J. M., Ostrovsky, D., Rodgers, A., Vugmeyster, L., Yao, L., & Qiang, W. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105196 · Cited by 12
“Amyloid deposits were found to colocalize with cell nucleus for both N2a and SH-SY5Y, consistent with previous reports of the nonspeci fi c intracellular distribution of A β deposits in the human neuroblastoma cell (25, 26).”
Nam, E., Lin, Y., Park, J., Do, H., Han, J., Jeong, B., Park, S., Lee, D. Y., Kim, M., Han, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202307182 · Cited by 12
Volloch, V., & Rits‐Volloch, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417586 · Cited by 13
Wang, X., Song, X., Takata, T., Miichi, Y., Yokono, K., & Sakurai, T. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.07.004 · Cited by 12
Morris, O. M., Röntgen, A., Toprakcioglu, Z., Cali, M. P., Dada, S., & Vendruscolo, M. (2025) · ACS Central Science · doi:10.1021/acscentsci.5c00614 · Cited by 12
Lee, E., Park, H., & Kim, S. (2024) · Molecules and Cells · doi:10.1016/j.mocell.2024.100089 · Cited by 12
“The uptake of extracellular amyloids has been implicated in the initiation of intracellular aggregate formation, which subsequently leads to neurotoxicity and transmission (Friedrich et al., 2010; Hu et al., 2009; Jin et al., 2016).”
Live Cell FRET Imaging Reveals Amyloid β-Peptide Oligomerization in Hippocampal Neurons
Gao, Y., Wennmalm, S., Winblad, B. G., Schedin‐Weiss, S., & Tjernberg, L. O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094530 · Cited by 11
“did not detect Aβ aggregation in SHSY5Y cells treated with 500 nM Aβ42 or below for 5 days, using agarose gel electrophoresis-SDS [16].”
BackgroundMethodResultInfluentialAβ31–35 Decreases Neprilysin-Mediated Alzheimer’s Amyloid-β Peptide Degradation
Leite, J. P., Lete, M. G., Fowler, S. A., Gimeno, A., Rocha, J. F., Sousa, S. F., Webster, C. I., Jiménez‐Barbero, J., & Gales, L. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00432 · Cited by 11
Pathways of hLL-3717-29 Aggregation Give Insight into the Mechanism of α-Amyloid Formation
Mitra, A., & Paul, S. (2023) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c04742 · Cited by 11
Alzheimer’s Disease Prevention and Treatment: Case for Optimism
Volloch, V., Olsen, B. R., & Rits‐Volloch, S. (2019) · Annals of Integrative Molecular Medicine · doi:10.33597/aimm.02-1008 · Cited by 11
“Beta-sheet-rich Aβ42 aggregates were observed to enter cells at low nanomolar concentrations [36].”
BackgroundMa, K., Xing, S., Luan, Y., Zhang, C., Liu, Y., Fei, Y., Zhang, Z., Liu, Y. U., & Chen, X. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.732429 · Cited by 12
Sex Hormones Protect Against Amyloid‐β Induced Oxidative Stress in the Choroid Plexus Cell Line Z310
Costa, A. R., Marcelino, H., Gonçalves, I., Quintela, T., Tomás, J., Duarte, A. C., Fonseca, A. M., & Santos, C. R. A. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12404 · Cited by 13
Visualizing Amyloid Assembly at the Nanoscale: Insights from Super‐Resolution Imaging
Bhuskute, K. R., Kikuchi, K., Luo, Z., & Kaur, A. (2024) · Analysis & Sensing · doi:10.1002/anse.202400001 · Cited by 10
Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System
Iida, A., Abe, M., Nochi, M., Soga, C., Unoura, K., & Nabika, H. (2021) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.1c00524 · Cited by 10
Volloch, V., & Rits‐Volloch, S. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230037 · Cited by 11
Kong, L.-X., & Zeng, C. (2017) · Biochemistry (Moscow) · doi:10.1134/s0006297917020079 · Cited by 9
“Recent reports have demonstrated that amyloid seeds form in cells after the cells take up an amyloidogenic peptide [6], and that preformed superoxide dismutase fibrils function as seeds to trigger amyloid formation of the protein in cells [7].”
BackgroundWang, Z., Sharda, N., Curran, G. L., Li, L., Lowe, V. J., & Kandimalla, K. K. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00549 · Cited by 10
Salazar, J., Poejo, J., Mata, A. M., Samhan-Arias, A. K., & Gutiérrez‐Merino, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042289 · Cited by 10
Mazargui, H., Lévêque, C., Bartnik, D., Fantini, J., Gouget, T., Melone, M. A. B., Funke, S. A., Willbold, D., & Perrone, L. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00814.x · Cited by 10
“According with a previous report (Hu et al., 2009), the extract of cells loaded with wt Ab seeded the aggregation of wt Ab in vitro (Fig.”
BackgroundMethodResultInfluentialγ‐secretase complexes containing caspase‐cleaved presenilin‐1 increase intracellular Aβ42/Aβ40 ratio
Hedskog, L., Petersen, C. H., Svensson, A., Welander, H., Tjernberg, L. O., Karlström, H., & Ankarcrona, M. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01208.x · Cited by 11
“Furthermore, it has been suggested that intracellular accumulation of A can form amyloid seeds that later will become extracellular plaques [6, 7].”
BackgroundWesén, E. V., Lundmark, R., & Esbjörner, E. K. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00053 · Cited by 9
Brown, C. N., Rumian, N. L., Tullis, J. E., Coultrap, S. J., & Bayer, K. U. (2022) · iScience · doi:10.1016/j.isci.2022.104368 · Cited by 9
“As Ab is internalized by neurons (Hu et al., 2009; Riad et al., 2020), the effect could be mediated by direct binding of Ab to CaMKII.”
BackgroundBender, T., & Dencher, N. A. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/7567959 · Cited by 9
“It was previously demonstrated that cellular uptake of Aβ1–42 is independent of the attached fluorophore and nonattached fluorophore does not go into the cell [40].”
BackgroundNath, S., Buell, A. K., & Barz, B. (2023) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp05961d · Cited by 9
Volloch, V., & Rits‐Volloch, S. (2019) · Annals of Integrative Molecular Medicine · doi:10.33597/aimm.02-1009 · Cited by 10
“Beta-sheet-rich Aβ42 aggregates were observed to enter cells at low nanomolar concentrations [111].”
BackgroundDeciphering the prion-like behavior of pathogenic protein aggregates in neurodegenerative diseases
Yoshida, S., & Hasegawa, T. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105307 · Cited by 9
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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