ArticleThe Journal of biological chemistry2011
Two distinct amyloid beta-protein (Abeta) assembly pathways leading to oligomers and fibrils identified by combined fluorescence correlation spectroscopy, morphology, and toxicity analyses.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 111 citations in OpenAlex.
- How does protein aggregate structure affect mechanisms of disaggregation?Biochemical Society transactions · 2025Review
- Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer's Pathogenesis.Molecular neurobiology · 2025Review
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
- Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer's Disease and Associated Amyloid-Disease Brain Tissue.ACS central science · 2024Article
- Review
- Cascade autohydrolysis of Alzheimer's Aβ peptides.Chemical science · 2023Article
- Aggregation of Disordered Proteins Associated with Neurodegeneration.International journal of molecular sciences · 2023Review
- Monosialotetrahexosylganglioside Promotes Early Aβ42 Oligomer Formation and Maintenance.ACS chemical neuroscience · 2022Article
- The Effect of Ethanol on Disassembly of Amyloid-βInternational journal of molecular sciences · 2022Article
- Alzheimer's Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway in brain vascular endothelial cells.iScience · 2021Article
- Emergence of Barrel Motif in Amyloid-β Trimer: A Computational Study.The journal of physical chemistry. B · 2020Article
- Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers.International journal of molecular sciences · 2020Review
- The Toxicity and Polymorphism of β-Amyloid Oligomers.International journal of molecular sciences · 2020Review
- NMR-based site-resolved profiling of β-amyloid misfolding reveals structural transitions from pathologically relevant spherical oligomer to fibril.The Journal of biological chemistry · 2020Article
- Elucidating the Molecular Determinants of Aβ Aggregation with Deep Mutational Scanning.G3 (Bethesda, Md.) · 2019Article
- Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion.iScience · 2019Article
- Origin of metastable oligomers and their effects on amyloid fibril self-assembly.Chemical science · 2018Article
- The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade.Journal of Alzheimer's disease : JAD · 2018Review
- Spreading of Pathology in Alzheimer's Disease.Neurotoxicity research · 2017Review
- A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers.Journal of neurochemistry · 2017Article
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Authors and funding
24 authors at 10 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nonfibrillar assemblies of amyloid β-protein (Aβ) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using Aβ labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical Aβ assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of ∼330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are ∼128 kDa (∼32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the Aβ(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying Aβ assembly steps at which inhibition may be beneficial.
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