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Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity
Open accessAbstract
The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.
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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 [18]
Experimental — accuracy not yet measuredIn the citing paper
“Endosomal Aβ42 labeling by immuno-EM has since been confirmed by other groups [49, 95, 143].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [49]
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Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation
Pilkington, E. H., Lai, M., Ge, X., Stanley, W. J., Wang, B., Wang, M., Käkinen, A., Sani, M., Whittaker, M. R., Gurzov, E. N., et al. (2017) · Biomacromolecules · doi:10.1021/acs.biomac.7b01301 · Cited by 79
Fruhwürth, S., Zetterberg, H., & Paludan, S. R. (2024) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2024.578342 · Cited by 77
D’Angelo, F., Vignaud, H., Martino, J. S. D., Salin, B., Devin, A., Cullin, C., & Marchal, C. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.010108 · Cited by 80
“It has been recently shown in a cellular model that bundles of A fibrils formed from soluble extracellular A penetrate the vesicular membrane and extend into the cytoplasm prior to cell death (Friedrich et al., 2010).”
Dehle, F. C., Ecroyd, H. W., Musgrave, I., & Carver, J. A. (2010) · Cell Stress and Chaperones · doi:10.1007/s12192-010-0212-z · Cited by 74
“intracellular phase of A? aggregation prior to extracellular fibril release (Friedrich et al. 2010) provides a plausible explanation for the collocation of a -crystallin with A? in the extracellular plaques associated with AD.”
BackgroundRöhr, D., Boon, B. D. C., Schuler, M., Kremer, K., Hoozemans, J. J. M., Bouwman, F. H., El-Mashtoly, S. F., Nabers, A., Großerueschkamp, F., Rozemuller, A. J. M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01091-5 · Cited by 77
“2B2), which might originate from parenchymal Aβ depositions or Aβ-enriched cells, which would align with descriptions of internalized Aβ prior to parenchymal infestation [13, 25, 33].”
BackgroundSugiura, Y., Ikeda, K., & Nakano, M. (2015) · Langmuir · doi:10.1021/acs.langmuir.5b03332 · Cited by 69
Banerjee, S., Hashemi, M., Zagorski, K., & Lyubchenko, Y. L. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00688 · Cited by 69
Amyloid β Peptides Aggregation in a Mixed Membrane Bilayer: A Molecular Dynamics Study
Zhao, L. N., Chiu, S.-W., Benoit, J., Chew, L. Y., & Mu, Y. (2011) · The Journal of Physical Chemistry B · doi:10.1021/jp2065985 · Cited by 67
Ding, Y. J., Zhao, J., Zhang, X., Wang, S., Viola, K. L., Chow, F. E., Zhang, Y., Lippa, C. F., Klein, W. L., & Gong, Y. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01140 · Cited by 68
Sivilia, S., Lorenzini, L., Giuliani, A., Gusciglio, M., Fernández, M., Baldassarro, V. A., Mangano, C., Ferraro, L., Pietrini, V., Baroc, M. F., et al. (2013) · BMC Neuroscience · doi:10.1186/1471-2202-14-44 · Cited by 65
“Intraneuronal Aβ severely affects neurons viability [8,9,47] and vulnerability to various neurotoxic challenges [48].”
BackgroundAn Imaging and Systems Modeling Approach to Fibril Breakage Enables Prediction of Amyloid Behavior
Xue, W., & Radford, S. E. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2013.10.034 · Cited by 64
Bharadwaj, P., Solomon, T., Malajczuk, C. J., Mancera, R. L., Howard, M. J., Arrigan, D. W. M., Newsholme, P., & Martins, R. N. (2018) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.03.015 · Cited by 63
Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease.
Morsy, A., & Trippier, P. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01530 · Cited by 54
Rahman, M. A., Rahman, M. S., Rahman, M. H., Rasheduzzaman, M., Mamun-Or-Rashid, A. N. M., Uddin, M. J., Rahman, M. R., Hwang, H., Pang, M., & Rhim, H. (2020) · Biomedicines · doi:10.3390/biomedicines9010005 · Cited by 68
“Moreover, fibrillary plaques are found in the intracellular spaces due to the aggregation of abnormal Aβ oligomers [13].”
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Moon, M., Hong, H.-S., Nam, D. W., Baik, S. H., Song, H., Kook, S.-Y., Kim, Y. S., Lee, J., & Mook-Jung, I. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-111778 · Cited by 60
“Based on our observations and previous reports [7–9, 11], we hypothesized that neurons that accumulate A may die and release A into the extracellular space, where it then becomes a hollow-type plaque and continues to grow through the accumulation of soluble A .”
Lumsden, A. L., Rogers, J. T., Majd, S., Newman, M., Sutherland, G. T., Verdile, G., & Lardelli, M. T. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00533 · Cited by 60
“While intracellular aggregation of Aβ may well contribute to plaque formation (Friedrich et al., 2010) and the rate of formation of an individual plaque is debated Frontiers in Neuroscience | www.frontiersin.org 2 August 2018 | Volume 12 | Article 533 (Burgold et al., 2011; Hefendehl et al., 2011),…”
BackgroundPlaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology
Wood, J. I., Wong, E., Joghee, R., Balbaa, A., Vitanova, K. S., Stringer, K. M., VanSchoiack, A., Phelan, S.-L. J., Launchbury, F., Desai, S., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111686 · Cited by 65
Banerjee, S., Hashemi, M., Lv, Z., Maity, S., Rochet, J., & Lyubchenko, Y. L. (2017) · Scientific Reports · doi:10.1038/srep45592 · Cited by 58
Pharmacological exploration of traditional plants for the treatment of neurodegenerative disorders
Wahid, M., Ali, A., Saqib, F., Aleem, A., Bibi, S., Afzal, K., Ali, A., Baig, A., Khan, S. A., & Asad, M. H. H. B. (2020) · Phytotherapy Research · doi:10.1002/ptr.6742 · Cited by 61
Petrov, A. M., Kasimov, M. R., & Zefirov, A. L. (2017) · Acta Naturae · doi:10.32607/20758251-2017-9-1-26-37 · Cited by 56
Kim, Y., Park, J., Lee, H., & Nam, J. (2016) · Scientific Reports · doi:10.1038/srep22173 · Cited by 58
Nanomechanics and intermolecular forces of amyloid revealed by four-dimensional electron microscopy
Fitzpatrick, A. W. P., Vanacore, G. M., & Zewail, A. H. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502214112 · Cited by 58
“In addition, whereas longer, mechanically stiff fibrils are able to disrupt (42) or perforate cell membranes (43), short fibrils, although shear weakened, are still sufficiently stiff (Y ∼ several hundred MPa) and pervasive to insert themselves into a lipid bilayer and stiffen the highly flexible (Y ∼ 1 MPa) cell memb…”
BackgroundBallesteros‐Álvarez, J., Nguyen, W., Sivapatham, R., Rane, A., & Andersen, J. K. (2022) · GeroScience · doi:10.1007/s11357-022-00708-y · Cited by 60
Novotny, R., Langer, F., Mahler, J., Skodras, A., Vlachos, A., Wegenast‐Braun, B. M., Kaeser, S. A., Neher, J. J., Eisele, Y. S., Pietrowski, M. J., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0258-16.2016 · Cited by 55
“Consistently, in previous work using a variety of cell lines and medium supplemented with A (albeit in at least tenfold higher concentration than in the present work), it was found that A aggregates occurred only in the presence of living cells (Friedrich et al., 2010), although again its in vivo activity was not test…”
ResultAmyloid-β oligomerization monitored by single-molecule stepwise photobleaching
Dresser, L. G., Hunter, P., Yendybayeva, F., Payne-Dwyer, A. L., Howard, J. A. L., Evans, G. J., Leake, M. C., & Quinn, S. D. (2020) · Methods · doi:10.1016/j.ymeth.2020.06.007 · Cited by 50
Self-folding and aggregation of amyloid nanofibrils
Paparcone, R., Cranford, S. W., & Buehler, M. J. (2011) · Nanoscale · doi:10.1039/c0nr00840k · Cited by 52
Assembly of α-synuclein aggregates on phospholipid bilayers
Lv, Z., Hashemi, M., Banerjee, S., Zagorski, K., Rochet, J., & Lyubchenko, Y. L. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.06.006 · Cited by 50
Prospects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies
Bittar, A., Sengupta, U., & Kayed, R. (2018) · npj Vaccines · doi:10.1038/s41541-018-0046-8 · Cited by 50
Cellular mechanism of fibril formation from serum amyloid A1 protein
Claus, S., Meinhardt, K., Aumüller, T., Puşcalău-Gîrţu, I., Linder, J., Haupt, C., Walther, P., Syrovets, T., Simmet, T., & Fändrich, M. (2017) · EMBO Reports · doi:10.15252/embr.201643411 · Cited by 48
“The latter mechanism was found in a cell model of Ab amyloid formation, in which intracellular fibrils distorted the compartment structure or pricked through the membrane to extend into the cytoplasm [43].”
Self-citation
Metadata
- Authors
- Friedrich, R. P., Tepper, K., Rönicke, R., Soom, M., Westermann, M., Reymann, K., Kaether, C., & Fändrich, M.
- Affiliations
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Leibniz Institute for Neurobiology (DE)
- Friedrich Schiller University Jena (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-01-19
- Volume
- 107
- Issue
- 5
- Pages
- 1942-1947
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2836607
- OpenAlex
- W2036172794
- Cited by
- 303
- References
- 63
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 20 · 2023: 20 · 2022: 13 · 2021: 21 · 2020: 23 · 2019: 11 · 2018: 30 · 2017: 28 · 2016: 15 · 2015: 18 · 2014: 8 · 2013: 24 · 2012: 13
- FWCI
- 15.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
- 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 plaque formation, amyloid-beta, Alzheimer's disease, multivesicular bodies, endocytosis, phagocytosis, cell death, amyloid-beta oligomers
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Chlorocebus aethiops, Freeze Fracturing, Humans, Intracellular Fluid, Microscopy, Electron, Scanning, Peptide Fragments, Amyloid beta-Peptides, Microscopy, Video, COS Cells, Mice, Plaque, Amyloid
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