Cited by 778Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers

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Kayed, Rakez, Head, Elizabeth, Sarsoza, Floyd, Saing, Tommy, Cotman, Carl W, Necula, Mihaela, Margol, Lawrence, Wu, Jessica +6 more·2007·Molecular Neurodegeneration

Abstract

Background: Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. Results: We immunized rabbits with a morphologically homogeneous population of Aβ42 fibrils. The resulting immune serum (OC) specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 × G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type II diabetes, demonstrating its generic specificity for amyloid fibrils. Conclusion: Since the fibril specific antibodies are conformation dependent, sequence-independent, and recognize epitopes that are distinct from those present in prefibrillar oligomers, they may have broad utility for detecting and characterizing the accumulation of amyloid fibrils and fibrillar type oligomers in degenerative diseases.

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  • A11 and 4G8 antibodies detect oligomeric and other protofibrillar conformations respectively.

    “We obtained high resolution confocal images of brain slices from CRND8 mice stained with A11 and 4G8 antibodies, which detect oligomeric and other protofibrillar conformations respectively (Lesné et al., 2006; Kayed et al., 2007).”

    From CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis (2010) · cites this paper as Kayed et al., 2007

    The Background and Results (pages not provided) support A11 as a detector of prefibrillar oligomers. But the Results report that 4G8 reacts with both fibrillar and prefibrillar samples, including monomer-sized material; they do not support describing it as a detector of a distinct protofibrillar conformation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured
  • As Aβ aggregates from monomers to oligomers and then fibrils, the conformation and antibody accessibility of peptide epitopes within Aβ can change.

    “As Aβ aggregates from monomers to oligomers and then fibrils, the conformation and antibody accessibility of peptide epitopes within Aβ can change.”

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Authors
Kayed, R., Head, E., Sarsoza, F., Saing, T., Cotman, C. W., Necula, M., Margol, L., Wu, J., Breydo, L., Thompson, J. L., Rasool, S., Gurlo, T., Butler, P., & Glabe, C. G.
Affiliations
  • University of California, Irvine (US)
  • University of California, Los Angeles (US)
Corresponding author
Glabe, Charles G
Venue
Molecular Neurodegeneration
Published
2007-09-26
Volume
2
Issue
1
Pages
18-18
ISSN
1750-1326 (ISSN-L)
OpenAlex
W2156193029
Cited by
773
References
28
Citations by year
2026: 21 · 2025: 35 · 2024: 36 · 2023: 42 · 2022: 32 · 2021: 41 · 2020: 57 · 2019: 35 · 2018: 44 · 2017: 40 · 2016: 43 · 2015: 52 · 2014: 45 · 2013: 65 · 2012: 59
FWCI
18.92
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Larry L. Hillblom Foundation
  • Cure Alzheimer's Fund
  • National Institutes of Health (AG16573, AG000538)
  • National Institute on Aging (P01AG000538, P50 AG 16573, AG 16573, AG-000538, P50AG016573)
  • National Institute of Neurological Disorders and Stroke (R01NS031230)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid fibrils, prefibrillar oligomers, epitope mapping, amyloid-beta 42, Alzheimer's disease, amylin, type 2 diabetes, amyloid deposits, immunization, thioflavin S, degenerative diseases

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