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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]
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“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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“1F), which are in the same range of intracellular A 42 concentrations reported in neurons of AD models (Hu et al., 2009; Hashimoto et al., 2010).”
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Janefjord, E., Mååg, J. L. V., Harvey, B. S., & Smid, S. D. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-013-9984-x · Cited by 118
Phagocytic Clearance in Neurodegeneration
Sokolowski, J. D., & Mandell, J. W. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.12.051 · Cited by 120
Barcoding heat shock proteins to human diseases: looking beyond the heat shock response
Kakkar, V., Meister-Broekema, M., Minoia, M., Carra, S., & Kampinga, H. H. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.014563 · Cited by 116
“Interestingly, evidence stating that intracellular Aβ-aggregation might precede extracellular plaque formation is accumulating, which increases the relevance of findings indicating that HSPs are able to prevent the initiation of aggregation in cells (72,73).”
BackgroundFuentealba, R. A., Liu, Q., Zhang, J., Kanekiyo, T., Hu, X., Lee, J.-M., LaDu, M. J., & Bu, G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011884 · Cited by 116
“extracellular space might represent a possible mechanism that contributes to intracellular Ab42 accumulation [10,11,12,13,14].”
BackgroundSelf-citationWesén, E. V., Jeffries, G. D. M., Dzebo, M. M., & Esbjörner, E. K. (2017) · Scientific Reports · doi:10.1038/s41598-017-02227-9 · Cited by 115
Lindberg, D. J., Wesén, E. V., Björkeroth, J., Rocha, S., & Esbjörner, E. K. (2017) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2017.05.012 · Cited by 113
Amyloid-β(1–42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity
Jin, S., Kedia, N., Illes‐Toth, E., Haralampiev, I., Prisner, S., Herrmann, A., Wanker, E. E., & Bieschke, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.691840 · Cited by 109
Resolution of Oligomeric Species during the Aggregation of Aβ1–40 Using 19F NMR
Suzuki, Y., Brender, J., Soper-Hopper, M. T., Krishnamoorthy, J., Zhou, Y., Ruotolo, B. T., Kotov, N. A., Ramamoorthy, A., & Marsh, E. N. G. (2013) · Biochemistry · doi:10.1021/bi400027y · Cited by 107
Retromer disruption promotes amyloidogenic APP processing
Sullivan, C. P., Jay, A. G., Stack, E. C., Pakaluk, M., Wadlinger, E., Fine, R. E., Wells, J. M., & Morin, P. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.04.002 · Cited by 103
Origin of metastable oligomers and their effects on amyloid fibril self-assembly
Hasecke, F., Miti, T., Perez, C., Barton, J., Schölzel, D., Gremer, L., Grüning, C. S. R., Matthews, G., Meisl, G., Knowles, T. P. J., et al. (2018) · Chemical Science · doi:10.1039/c8sc01479e · Cited by 103
Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease
Mariani, M. M., Malm, T., Lamb, R., Jay, T. R., Neilson, L., Casali, B., Medarametla, L., & Landreth, G. E. (2017) · Scientific Reports · doi:10.1038/srep42270 · Cited by 98
Stability matters, too – the thermodynamics of amyloid fibril formation
Buell, A. K. (2022) · Chemical Science · doi:10.1039/d1sc06782f · Cited by 99
Sequestration of Toxic Oligomers by HspB1 as a Cytoprotective Mechanism
Ojha, J., Masilamoni, G. J., Dunlap, D. D., Udoff, R. A., & Cashikar, A. G. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01187-10 · Cited by 99
“neuroblastoma cells (29), microglia (42), and astrocytes (1, 46).”
BackgroundSmethurst, P., Sidle, K. C. L., & Hardy, J. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12206 · Cited by 99
Brender, J., Krishnamoorthy, J., Sciacca, M. F. M., Vivekanandan, S., D’Urso, L., Chen, J., Rosa, C. L., & Ramamoorthy, A. (2015) · The Journal of Physical Chemistry B · doi:10.1021/jp511758w · Cited by 98
Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation
Onos, K. D., Uyar, A., Keezer, K. J., Jackson, H. M., Preuss, C., Acklin, C. J., O’Rourke, R., Buchanan, R., Cossette, T. L., Sukoff Rizzo, S. J., et al. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1008155 · Cited by 93
Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease
Rudajev, V., & Novotny, J. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.937056 · Cited by 94
“The interaction was enhanced under acidic conditions, which corresponds to endosomal environment in which Aβ cytotoxic effects are expected to occur after Aβ endocytosis (Hu et al., 2009; Cuco et al., 2016).”
BackgroundAmadoro, G., Corsetti, V., Atlante, A., Florenzano, F., Capsoni, S., Bussani, R., Mercanti, D., & Calissano, P. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.08.001 · Cited by 95
“…(Chong et al., 2006), in parallel to a reduction of synapthophisin immunoreactivity (Kuperstein et al., 2010), although the intracellular compartments can also accumulate A at higher M concentrations favoring thus the local formation of its aggregated toxic conformations (Hu et al., 2009).”
BackgroundCellular Strategies for Regulating Functional and Nonfunctional Protein Aggregation
Gsponer, J. A., & Babu, M. M. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.09.036 · Cited by 92
“This can be achieved, for example, by specific regulatory proteins that ‘‘scaffold’’ aggregation-prone proteins in a particular location or by confinement of the protein within cellular compartments (Brangwynne et al., 2009; Decker et al., 2007; Fowler et al., 2006; Harper and Lansbury, 1997; Hu et al., 2009; Li et al…”
BackgroundShih, Y., Tu, L., Chang, T.-Y., Ganesan, K., Chang, W.-W., Chang, P.-S., Fang, Y.-S., Lin, Y.-T., Jin, L., & Chen, Y. (2020) · Nature Communications · doi:10.1038/s41467-020-19786-7 · Cited by 92
Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.
Arbor, S., LaFontaine, M., & Cumbay, M. G. (2016) · Europe PMC (PubMed Central) · Cited by 94
Li, M., Guan, Y., Zhao, A., Ren, J., & Qu, X. (2017) · Theranostics · doi:10.7150/thno.18459 · Cited by 90
“ThS is a standard fluorescent stain that specifically binds to amyloid protein deposits, leading to emit yellow fluorescence under ultraviolet light[61-64].”
BackgroundFlores‐Bellver, M., Mighty, J., Aparicio‐Domingo, S., Li, K. V., Shi, C., Zhou, J., Cobb, H., McGrath, P. S., Michelis, G., Lenhart, P., et al. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12165 · Cited by 89
“In addition, when Aβ concentration overwhelms the lysosomal degradation compartment leads to Aβ aggregation (Hu et al., 2009; Li et al., 2012) and propagation of toxic Aβ aggregates via EVs (Riva et al.”
BackgroundProtective Effects of Positive Lysosomal Modulation in Alzheimer's Disease Transgenic Mouse Models
Butler, D., Hwang, J., Estick, C., Nishiyama, A., Kumar, S. S., Baveghems, C. L., Young-Oxendine, H. B., Wisniewski, M. L., Charalambides, A., & Bahr, B. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020501 · Cited by 92
Aβ Internalization by Neurons and Glia
Mohamed, A., & Chaves, E. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/127984 · Cited by 94
“Intraneuronal Aβ accumulates within the endosomal/lysosomal system, in vesicles sometimes identified as lysosomes [13, 40, 56, 64, 71, 82, 123] and some others as late endosomes/multivesicular bodies (MVBs) [30, 124–126].”
BackgroundPacheco‐Quinto, J., & Eckman, E. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.422964 · Cited by 92
“There was no increase in iA accumulation following treatment with 5 nM A , suggesting that if SH-SY5Y cells endocytose A (34, 35), any internalized peptide is degraded by non-PA sensitive proteases.”
BackgroundSmall Liposomes Accelerate the Fibrillation of Amyloid β (1–40)
Terakawa, M. S., Yagi, H., Adachi, M., Lee, Y., & Goto, Y. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.592527 · Cited by 89
Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A
Willén, K., Edgar, J. R., Hasegawa, T., Tanaka, N., Futter, C. E., & Gouras, G. K. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0203-y · Cited by 86
“In line with this, it was shown in SHSY5Y cells that synthetic Aβ1-42 added to cell culture medium at 1 μM was taken up and formed aggregates of Aβ inside these cells, while only monomers could be found in the cell culture medium even after 5 days [45].”
BackgroundItakura, M., Nakajima, H., Kubo, T., Semi, Y., Kume, S., Higashida, S., Kaneshige, A., Kuwamura, M., Harada, N., Kita, A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.669291 · Cited by 85
“The concentration of A in vivo is reported to be 5 nM (51, 52), whereas aggregation in vitro requires a concentration nearly 3 orders of magnitude greater than in vivo values (53).”
BackgroundLambeth, T. R., Riggs, D. L., Talbert, L. E., Tang, J. Y., Coburn, E., Kang, A. S., Noll, J. M., Augello, C. J., Ford, B. D., & Julian, R. R. (2019) · ACS Central Science · doi:10.1021/acscentsci.9b00369 · Cited by 82
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“2,3 Earlier, we demonstrated that epigallocatechin gallate (EGCG), a polyphenol extracted from green tea, can prevent the formation of fibrillar deposits of A b and other amyloidogenic proteins.”
Harvey, B. S., Ohlsson, K. S., Mååg, J. L. V., Musgrave, I. F., & Smid, S. D. (2012) · NeuroToxicology · doi:10.1016/j.neuro.2011.12.015 · Cited by 82
Tau prion-like propagation: state of the art and current challenges
Dujardin, S., & Hyman, B. T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-32-9358-8_23 · Cited by 84
Ubiquitin, Autophagy and Neurodegenerative Diseases
Watanabe, Y., Taguchi, K., & Tanaka, M. (2020) · Cells · doi:10.3390/cells9092022 · Cited by 86
“However, Aβ oligomers also accumulate intracellularly through endocytosis of secreted Aβ [12].”
BackgroundRiad, A., Lengyel-Zhand, Z., Zeng, C., Weng, C.-C., Lee, V. M.-Y., Trojanowski, J. Q., & Mach, R. H. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01988-1 · Cited by 81
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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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