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Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths
Open accessAbstract
One of the clinical manifestations of Alzheimer's disease is the deposition of the 39-43 residue amyloid-beta (A beta) peptide in aggregated fibrils in senile plaques. Characterization of the aggregation behavior of A beta is one of the critical issues in understanding the role of A beta in the disease process. Using solution hydrodynamics, A beta was observed to form three types of species in phosphate-buffered saline: insoluble aggregates with sedimentation coefficients of approximately 50,000 S and molecular masses of approximately 10(9) Da, "soluble aggregates" with sedimentation coefficients of approximately 30 S and masses of approximately 10(6) Da, and monomer. When starting from monomer, the aggregation kinetics of A beta 1-40 (A beta 40) and A beta 1-42 (A beta 42), alone and in combination, reveal large differences in the tendency of these peptides to aggregate as a function of pH and other solution conditions. At pH 4.1 and 7.0-7.4, aggregation is significantly slower than at pH 5 and 6. Under all conditions, aggregation of the longer A beta 42 was more rapid than A beta 40. Oxidation of Met-35 to the sulfoxide in A beta 40 enhances the aggregation rate over that of the nonoxidized peptide. Aggregation was found to be dependent upon temperature and to be strongly dependent on peptide concentration and ionic strength, indicating that aggregation is driven by a hydrophobic effect. When A beta 40 and A beta 42 are mixed together, A beta 40 retards the aggregation of A beta 42 in a concentration-dependent manner. Shorter fragments have a decreasing ability to interfere with A beta 42 aggregation. Conversely, the rate of aggregation of A beta 40 can be significantly enhanced by seeding slow aggregating solutions with preformed aggregates of A beta 42. Taken together, the inhibition of A beta 42 aggregation by A beta 40, the seeding of A beta 40 aggregation by A beta 42 aggregates, and the chemical oxidation of A beta 40 suggest that the relative abundance and rates of production of different-length A beta and its exposure to radical damage may be factors in the accumulation of A beta in plaques in vivo.
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“The increased Aβ 42:40 ratio in oligodendrocytes could contribute to the high proportion of soluble aggregates [28,42,43]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [42]
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Metadata
- Authors
- Snyder, S. W., Ladror, U. S., Wade, W. S., Wang, G. T., Barrett, L. W., Matayoshi, E. D., Huffaker, H. J., Krafft, G. A., & Holzman, T. F.
- Affiliations
- Abbott (United Kingdom) (GB)
- Corresponding author
- Holzman, T.F.
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 1994-09
- Volume
- 67
- Issue
- 3
- Pages
- 1216-1228
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC1225478
- OpenAlex
- W2024559246
- Cited by
- 381
- References
- 55
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 17 · 2023: 5 · 2022: 9 · 2021: 20 · 2020: 8 · 2019: 12 · 2018: 9 · 2017: 18 · 2016: 13 · 2015: 9 · 2014: 10 · 2013: 18 · 2012: 17
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- National Institutes of Health (7p01ag010481-05)
- National Institute on Aging (AG10481)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta aggregation, Alzheimer's disease, Aβ40, amyloid-beta 42, peptide length, aggregation kinetics, hydrophobic effect, seeding, aggregation inhibition, pH dependence, ionic strength, amyloid plaques
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Biophysics, Humans, Kinetics, Microscopy, Electron, Molecular Sequence Data, Polymers, Protein Conformation, Solutions, Amyloid beta-Peptides, Neurofibrillary Tangles, Macromolecular Substances, Biophysical Phenomena, In Vitro Techniques
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