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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Microglial lysosomes provide a suitable environment to facilitate Aβ aggregation, potentially contributing to the onset of plaque pathology.
“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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“Aβ peptides are collected in intraluminal vesicles within MVBs and, upon fusion with the PM, the intraluminal vesicles are released into the extracellular space as exosomes (Rajendran et al., 2006; Sharples et al., 2008; Hu et al., 2009; Figure 1).”
BackgroundLi, J., Kanekiyo, T., Shinohara, M., Zhang, Y., LaDu, M. J., Xu, H., & Bu, G. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.420224 · Cited by 175 · see citing works
“In vitro seeding assay was performed as described previously (17).”
MethodSelf-citationActivation of PERK Signaling Attenuates Aβ-Mediated ER Stress
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“Previous reports have been shown that extracellularly applied Ab can be taken up by cultured neuronal cell lines [27,29,30] and colocalized in the endosomes/lysosomes or mitochondria [31,32].”
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Critical aggregation concentration for the formation of early Amyloid-β (1–42) oligomers
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“and HiLyte Fluor 488-β-amyloid(1-42) from AnaSpec Inc.”
Recent progress in understanding Alzheimer's β-amyloid structures
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“However, when excess amounts of Ab are internalized, it can aggregate in lysosomes, likely providing “seeds” to initiate further Ab aggregation (67, 68).”
BackgroundSelf-citationCell Biology of Prions and Prionoids: A Status Report
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Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells
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“It is then tempting to speculate, as observed separately for exosomes (Yuyama et al., 2014) and ApoE (Li et al., 2012), that exosomes harboring ApoE would favor endocytosis and targeting of Ab to MVEs and provide a favorable environment for Ab seeding and neutralization (Hu et al., 2009).”
BackgroundAlpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease
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Structural insights into α-synuclein monomer–fibril interactions
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“Accelerated prion-like protein aggregation is found, for example, in the mildly acidic chemical environment of endosomes (43).”
Esbjörner, E. K., Chan, F., Rees, E. J., Erdélyi, M., Luheshi, L. M., Bertoncini, C. W., Kaminski, C. F., Dobson, C. M., & Schierle, G. S. K. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.03.014 · Cited by 138 · see citing works
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“protein (1-42) by atomic force microscopy.”
BackgroundSelf-citationDays to criterion as an indicator of toxicity associated with human Alzheimer amyloid‐β oligomers
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Impact of membrane curvature on amyloid aggregation
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“The initial lag-phase can be circumvented by the presence of pre-existing aggregates that can act as seeds for amyloid formation (Lansbury, 1997; Hu et al., 2009; Langer et al., 2011; Hamaguchi et al., 2012).”
BackgroundAdvances in the Simulation of Protein Aggregation at the Atomistic Scale
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“Homeostatic microglia uptake extracellular A β and concentrate it within endosomes and lysosomes at an acidic pH 54,55 , which could generate intracellular high molecular weight species 56,57 .”
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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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Phagocytic Clearance in Neurodegeneration
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“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 · see citing works
“extracellular space might represent a possible mechanism that contributes to intracellular Ab42 accumulation [10,11,12,13,14].”
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Amyloid-β(1–42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity
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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 · see citing works
Retromer disruption promotes amyloidogenic APP processing
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Origin of metastable oligomers and their effects on amyloid fibril self-assembly
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Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease
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Stability matters, too – the thermodynamics of amyloid fibril formation
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Sequestration of Toxic Oligomers by HspB1 as a Cytoprotective Mechanism
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“neuroblastoma cells (29), microglia (42), and astrocytes (1, 46).”
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Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation
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Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease
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“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).”
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“…(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 91 · see citing works
“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 90 · see citing works
Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A
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“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].”
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“ThS is a standard fluorescent stain that specifically binds to amyloid protein deposits, leading to emit yellow fluorescence under ultraviolet light[61-64].”
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“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 88 · see citing works
Aβ Internalization by Neurons and Glia
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“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)
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“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).”
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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.”
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“However, Aβ oligomers also accumulate intracellularly through endocytosis of secreted Aβ [12].”
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- 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
- Health Sciences › Medicine › Physiology › 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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