Small Molecule Inhibitors of Aggregation Indicate That Amyloid β Oligomerization and Fibrillization Pathways Are Independent and Distinct
Open accessAbstract
Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.
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L1 and L2 were designed following the linkage approach and contain metal-binding N-(2-pyridylmethyl)amine groups and amyloid-interacting 2-phenylbenzothiazole and o-vanillin molecular fragments.
“Reported herein are two new BFCs, L1 and L2, that were designed following the linkage approach and contain metal-binding N-(2-pyridylmethyl)amine groups and amyloid-interacting 2-phenylbenzothiazole and o-vanillin molecular fragments (Scheme 2).59”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [59]
The Experimental Procedures list o-vanillin among compounds tested for effects on amyloid-β aggregation, and the Discussion identifies it as inhibiting both oligomerization and fibrillization (page unavailable). The copy does not describe L1 or L2, the linkage approach, or the claimed composition of those new compounds; it also does not establish the specific role of a 2-phenylbenzothiazole fragment. (LLM, conf=0.82)
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- Authors
- Necula, M., Kayed, R., Milton, S., & Glabe, C. G.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Glabe, Charles G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 282
- Issue
- 14
- Pages
- 10311-10324
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2050146983
- Cited by
- 680
- References
- 9
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 11 · 2023: 16 · 2022: 17 · 2021: 24 · 2020: 31 · 2019: 19 · 2018: 33 · 2017: 31 · 2016: 47 · 2015: 40 · 2014: 50 · 2013: 46 · 2012: 68
- FWCI
- 35.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health (5r01ns038298-05)
- National Institute of Neurological Disorders and Stroke (NS 38298)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Keywords
- amyloid-beta, oligomerization, fibrillization, small molecule inhibitors, Alzheimer's disease, amyloid plaques, protein aggregation, aggregation inhibitors, therapeutic target
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Humans, Thermodynamics, Amyloid beta-Peptides, Protein Structure, Quaternary, Plaque, Amyloid
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